2-(Substituted-phenyl)amino-imidazoline derivatives

ABSTRACT

This invention relates to IP receptor antagonists selected from the group of compounds represented by Formula I:  
                 
 
     where:  
     R 1  is a group represented by formula (A), (B) or (C);  
                 
 
       d other substituents as defined in the specification, and their pharmaceutically acceptable  ts or crystal forms thereof; and pharmaceutical compositions containing them; and methods   their use as therapeutic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority under 35 U.S.C. 119(e) toco-pending U.S. Provisional Application No. 60/089,916, filed Jun. 19,1998; No. 60/088,015, filed Jun. 4, 1998; and No. 60/057,808, filed Sep.4, 1997.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to IP receptor antagonists, especially tocertain 2-(substituted-phenyl)amino-imidazoline derivatives;pharmaceutical compositions containing them; and methods for their useas therapeutic agents.

[0004] 2. Background Information and Related Disclosures

[0005] Prostaglandins or prostanoids (PG) are a group of biologicallyactive compounds derived from membrane phospholids and are formed fromcertain polyunsaturated fatty acids. They fall into several main classesdesignated by letters including D, E, F, G, H, and I (prostacyclin). Themain classes are further subdivided as indicated by subscripts 1, 2, or3, which reflect the fatty acid precursor, for example PGE₁ or PGE₂.Prostanoids are ubiquitously produced and the rate of their productionusually increases in response to diverse stimuli. They thereby exhibit awide variety of pharmacological properties.

[0006] The diversity of effects of prostanoids can be explained by theexistence of a number of distinct receptors that mediate their action.The receptors have been named for the natural prostaglandin for whichthey have the greatest affinity and have been divided into five maintypes, designated as DP (PGD₂), FP (PG₂ _(α) ), IP (PGI₂), TP (TXA₂),AND EP (PGE₂). Additional information relating to prostaglandins andtheir receptors are described in Goodman & Gillman's, ThePharmacological Basis of Therapeutics, ninth edition, McGraw-Hill, NewYork, 1996, Chapter 26, pages 601-616.

[0007] Prostanoids are generated by most cells in response tomechanical, thermal or chemical injury and inflammatory insult, and areresponsible for the sensitization or direct activation of nearby sensorynerve endings. The hyperalgesic effects (an increased responsiveness toa stimulus that is normally painful) of several prostanoids have beenreported in several inflammatory models of nociception. Even though PGE₂has attained wide recognition as the primary mediator of hyperalgesia,significant quantities of other prostanoids, including PGI₂, arereleased by injury or inflammation. Indeed, when the effects of PGE₂ andPGI₂ on sensory neurons are compared directly, PGI₂ is equally or moreeffective as a hyperalgesic or sensitizing agent both in vivo and invitro assays. However, to date, there have been no selective receptorantagonists which could unequivocally characterize the prostanoidreceptor subtype(s) that mediate the sensitizing effects of PGE₂ orPGI₂.

[0008] When the intrinsic instability and pharmacokinetic properties ofPGI₂ are taken into account, a preponderance of in vivo analgesiastudies in rodents suggest that PGI₂ plays a major role in the inductionof hyperalgesia. Likewise, in vitro studies provide substantial evidenceto suggest that IP receptors act as important modulators of sensoryneuron function. Since IP receptors in sensory neurons are coupled toactivation of both adenylyl cyclase and phospholipase C, and hence,cAMP-dependent protein kinase and protein kinase C, these receptors canexert powerful effects on ion channel activity and thus neurotransmitterrelease.

[0009] Recent compelling evidence for a prominent role for IP(PGI₂-preferring) receptors in inflammatory pain has been obtained fromrecent studies in transgenic mice lacking the IP receptor (T. Murata etal., Nature 1997, 388, 678-682). In these animals, the aceticacid-induced writhing response or the carrageenan-induced paw edema wasreduced to levels similar to those seen with administration ofindomethacin in wild-type mice. In contrast, spinal nociceptive reflexesmeasured by the tail-flick and hot-plate test were normal. The modestwrithing response induced by PGE₂ was unchanged in the transgenicanimals.

[0010] Based upon these observations, the compounds of the presentinvention are expected to be effective anti-nociceptive agents.

[0011] In addition to being mediators of hyperalgesia, prostanoids areknown to be generated locally in the bladder in response to physiologicstimuli such as stretch of the detrusor smooth muscle, injuries of thevesical mucosa, and nerve stimulation (K. Anderson, PharmacologicalReviews 1993, 45(3), 253-308). PGI₂ is the major prostanoid releasedfrom the human bladder. Several lines of evidence suggest thatprostanoids may be the link between detrusor muscle stretch produced bybladder filling and activation of C-fiber afferents by bladderdistension. It has been proposed that prostanoids may be involved in thepathophysiology of bladder disorders, e.g., bladder outlet obstruction,and conditions associated with urinary incontinence such as urgeincontinence, stress incontinence, and bladder hyperreactivity.Therefore, antagonists of prostanoid IP receptors are expected to beuseful in the treatment of such conditions.

[0012] Certain 2-(substituted-phenyl)amino-imidazoline compounds havebeen exemplifed in the patent literature. For example, European PatentNo. 0 017 484 B1 (Fujisawa Pharmaceutical) discloses compounds usefulfor treatment of hypertensive, inflammatory and gastrointestinaldisorder and relief from pain of various origins; U.S. Pat. No.4,287,201 (Olson et al.) discloses compounds useful in delaying theonset of egg production in young pullets, interrupting egg production inmature hens, and in producing an artificial molt; U.S. Pat. No.4,396,617 (Dolman and Kuipers) discloses fungicides active against rustof beans, brown rust of wheat and mildew on cereals; U.S. Pat. No.4,889,868 (Huang) discloses lipoxygenase and phospholipase C inhibitorsand platelet-activating factor receptor antagonists useful for thetreatment of inflammatory or allergic conditions and myocardialinfarctions; U.S. Pat. No. 5,326,776 (Winn et al.) discloses compoundsthat are angiotensin II receptor antagonists; British Patent ApplicationNo. GB 2 038 305 (Duphar International Research) discloses compoundsthat can be used to inhibit growth of side shoots tobacco or tomatoplants, or inhibit lawn growth, or dwarf ornamental plants; and PCTPublished Application No. WO 96/30350 (Fujisawa Pharmaceutical)discloses compounds useful as a medicament for prophylactic andtherapeutic treatment of nitric oxide synthase-mediated diseases.

[0013] The disclosures of these and other documents referred tothroughout this application are incorporated herein by reference.

SUMMARY OF THE INVENTION

[0014] This invention provides compounds represented by Formula I:

[0015] wherein:

[0016] R¹ is a group represented by formula (A), (B) or (C);

[0017] wherein:

[0018] X is independently in each occurrence S, O or N;

[0019] R² and R⁴ are each independently in each occurrence:

[0020] (1) hydrogen,

[0021] (2) alkyloxy, or

[0022] (3) halogen;

[0023] R³ is independently in each occurrence:

[0024] (1) alkyl,

[0025] (2) cycloalkyl,

[0026] (3) halogen,

[0027] (4) heterocyclyl,

[0028] (5) —NR⁸R⁹,

[0029] (6) —(CH₂)_(m)CONR⁸R⁹, wherein m is an integer from 0 to 3,

[0030] (7) —(CH₂)_(m)SO₂NR⁸R⁹, wherein m is an integer from 0 to 3,

[0031] (8) —(CH₂)_(m)NR⁷COR⁹, wherein m is an integer from 0 to 3,

[0032] (9) —(CH₂)_(m)NR⁷SO₂R⁹, wherein m is an integer from 0 to 3,

[0033] (10) —(CH₂)_(m)NR⁷C(V)NR⁸R⁹, wherein V is S or O, and m is aninteger from 0 to 3,

[0034] (11) —(CH₂)_(m)OY wherein m is an integer from 0 to 3, and Y is:

[0035] hydrogen, alkyl, alkyloxyalkyl, cycloalkyl, haloalkyl,hydroxyalkyl, heterocyclyl, or carboxyalkyl, or

[0036] (12) —O(CH₂)_(n)Z wherein n is an integer from 1 to 4 and Z is:

[0037] cycloalkyl, hydroxyalkyl, cycloalkyloxy, heterocyclyl, aryloxy,heteroaryl, —COR⁹, —CONR⁸R⁹, —SO₂R⁹, —SO₂NR⁸R⁹, —NR⁷SO₂R⁹, orunsubstituted aryl or mono-, di-, or tri-substituted aryl, thesubstituents being independently selected from alkyl, halogen, oralkyloxy;

[0038] R⁵ is independently in each occurrence:

[0039] (1) —(CH₂)_(m)OY wherein m is an integer from 0 to 3, and Y is:

[0040] hydrogen, alkyl, alkyloxyalkyl, cycloalkyl, haloalkyl,hydroxyalkyl, heterocyclyl, or carboxyalkyl, or

[0041] (2) —O(CH₂)_(n)Z wherein n is an integer from 1 to 4, and Z is:

[0042] cycloalkyl, hydroxyalkyl, cycloalkyloxy, heterocyclyl, aryloxy,heteroaryl, —COR⁹, —CONR⁸R⁹, —SO₂R⁹, —SO₂NR⁸R⁹, or —NR⁷SO₂R⁹, orunsubstituted aryl or mono-, di-, or tri-substituted aryl, thesubstituents being independently selected from alkyl, halogen, oralkyloxy;

[0043] R⁶ is independently in each occurrence:

[0044] (1) hydrogen,

[0045] (2) —COR⁹,

[0046] (3) —CONR⁸R⁹,

[0047] (4) —C(V)NR⁸R⁹ wherein V is O or S,

[0048] (5) —SO₂R⁹, or

[0049] (6) —SO₂NR⁸R⁹;

[0050] R⁷ and R⁸ are each independently in each occurrence:

[0051] (1) hydrogen,

[0052] (2) alkyl, or

[0053] (3) hydroxyalkyl;

[0054] R⁹ is independently in each occurrence:

[0055] (1) alkyl,

[0056] (2) cycloalkyl,

[0057] (3) arylalkyl,

[0058] (4) hydroxyalkyl,

[0059] (5) haloalkyl,

[0060] (6) heterocyclyl,

[0061] (7) unsubstituted aryl or mono-, di-, or tri-substituted aryl,the substituents being independently selected from alkyl, halogen, oralkyloxy, or

[0062] (8) heteroaryl;

[0063] or R⁸ and R⁹ are taken together with the nitrogen to which theyare attached to form a 5- or 6-membered monocyclic saturated orunsaturated ring, and in which the ring is optionally substituted orunsubstituted with oxo;

[0064] or R⁷ and R⁹ are taken together with the nitrogen to which theyare attached to form a 5- or 6-membered monocyclic saturated orunsaturated ring, and in which the ring is optionally substituted orunsubstituted with oxo;

[0065] or a pharmaceutically acceptable salt or a crystal form thereof.

[0066] This invention further provides pharmaceutical compositionscontaining as an ingredient a therapeutically effective amount of acompound of Formula I or its pharmaceutically acceptable salt or acrystal form thereof, in admixture with one or more suitable carriers.

[0067] This invention further provides a method for treating painconditions from a wide variety of causes, including but not limited to,inflammatory pain, surgical pain, visceral pain, dental pain,premenstrual pain, central pain, pain due to burns, migraine or clusterheadaches, nerve injury, neuritis, neuralgias, poisoning, ischemicinjury, interstitial cystitis, cancer pain, viral, parasitic orbacterial infection, and post-traumatic injuries (including fracturesand sports injuries); inflammation from a variety of causes, includingbut not limited to, bacterial, fungal or viral infections, rheumatoidarthritis, osteoarthritis, surgery, bladder infection or idiopathicbladder inflammation, over-use, old age, nutritional deficiencies,prostatis, conjunctivitis, pain associated with functional boweldisorders such as irritable bowel syndrome; and additionally fortreating bladder disorders associated with bladder outlet obstruction,and urinary incontinence (including urge incontinence, stressincontinence, and bladder hyperreactivity); asthma; and septic shock inmammals comprising administering to a mammal in need of atherapeutically effective amount of a compound of Formula I or itspharmaceutically acceptable salt or a crystal form thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0068]FIG. 1 shows the X-ray diffraction pattern of Crystal Form I of2-[4-(4-isoproxybenzyl)phenyl]amino-imidazoline sulfate.

[0069]FIG. 2 shows the X-ray diffraction pattern of Crystal Form II of2-[4-(4-isoproxybenzyl)phenyl]amino-imidazoline sulfate.

DETAILED DESCRIPTION OF THE INVENTION

[0070] Definitions

[0071] Unless otherwise stated, the following terms used in thespecification and claims have the meanings given below:

[0072] “Alkyl” means a monovalent branched or unbranched saturatedhydrocarbon radical having from one to eight carbon atoms inclusive,such as methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl,tert-butyl, pentyl, n-hexyl, and the like.

[0073] “Cycloalkyl” means a monovalent saturated carbocyclic radicalhaving from three to fourteen carbon atoms inclusive, such ascyclopropylmethyl, cycylopropylethyl, cyclopropyl, cyclobutyl,3-ethylcyclobutyl, cyclopentyl, cyclopentyl, cycloheptyl, and the like.

[0074] “Alkyloxy” means a radical —OR where R is alkyl as defined above,optionally substituted with one or more alkyloxy groups. Examplesinclude, but are not limited to, methoxy, ethoxy, isopropoxy, secbutoxy,isobutoxy, 2-ethoxy-1-(ethoxymethyl)ethoxy, and the like.

[0075] “Cycloalkyloxy” means a radical —OR where R is cycloalkyl asdefined above, for example cyclopentyloxy, cyclohexyloxy, and the like.

[0076] “Hydroxyalkyl” means a linear monovalent hydrocarbon radical ofone to four carbons or a branched monovalent hydrocarbon radical ofthree or four carbon atoms substituted with one or two hydroxy groups,provided that if two hydroxy groups are present, they are not both onthe same carbon atom. Examples of hydroxyalkyl radicals include, but arenot limited to hydroxymethyl, 1-hydroxymethyl-ethyl, 2-hydroxypropyl,3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl,2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, and the like, preferably2-hydroxyethyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0077] “Alkyloxyalkyl” means hydroxyalkyl where the hydrogen atom(s) orone or the both hydroxy groups are replaced by C₁ alkyl, for example2-methoxyethyl, 3-methoxy-butyl, 2-methoxymethyl, 2-isopropoxy-ethyl or2-ethoxy-1-(ethoxymethyl)ethyl, and the like.

[0078] “Carboxyalkyl” means the radical —RCOOH where R is alkyl asdefined above, for example 2-propionic acid, 3-butanoic acid, and thelike.

[0079] “Aryl” means a monocyclic aromatic hydrocarbon radical of five orsix ring atoms, or a 9 to 14-membered bicyclic or tricyclic ring systemin which at least one ring is aromatic in nature. Examples of arylradicals include, but are not limited to, benzyl, phenyl, naphthyl, andthe like.

[0080] “Aryloxy” means a radical —OR where R is aryl as defined above,e.g., phenoxy, or the like.

[0081] “Arylalkyl” means the radical R^(a)R^(b)—where R^(a) is aryl asdefined above, and R^(b) is alkyl as defined above, for example benzyl,phenethyl, 3-phenylpropyl, and the like.

[0082] “Heteroaryl” means a monocyclic aromatic ring or a 9 to14-membered bicyclic ring system in which at least one ring is aromaticin nature, and includes heterocycles having one, two or threeheteroatoms within the ring, chosen from nitrogen, oxygen, and sulfur.Examples of heteroaryl radicals include, but are not limited to,thienyl, imidazolyl, pyridinyl, pyrazinyl, and the like.

[0083] “Heterocylyl” means a monovalent saturated carbocyclic radicalhaving a five, six or seven ring atoms of which one or two are selectedfrom nitrogen, oxygen or sulfur. Examples of heterocyclyl radicalsinclude, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl,[1,3]dioxan-5-yl, 5-methyl-[1,3]dioxan-5-yl, morpholino, imidazolinyl,piperidinyl, pyrrolidinyl, pyrrolidin-2-one, pyrrolidin-2,3-dione, andthe like; most preferably tetrahydropyranyl.

[0084] “Halogen” means fluoro, bromo, chloro and iodo, preferably fluoroand chloro.

[0085] “Haloalkyl” means alkyl substituted with one to three fluorine orchlorine atoms, for example chloromethyl, trifluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.

[0086] “Amino-protecting group” means a protecting group that preservesa reactive amino grouop that otherwise would be modified by certainchemical reactions. Amino-protecting groups commonly used include thosewhich are well-known in the art, for example benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, trialkylsilycarboxyl,trifluoromethylcarbonyl, p-nitrobenzyloxycarbonyl, N-tert-butoxycarbonyl(BOC), and the like. Certain amino-protecting groups are more preferredover others because of the relative ease of removal.

[0087] “Optional” or “optionally” means that the subsequently describedevent or circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optional bond” means that the bondmay or may not be present and that the description includes both singleand double bonds.

[0088] “Inert organic solvent” or “inert solvent” means a solvent inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform (CHCl₃), methylenechloride or dichloromethane (CH₂Cl₂), dichloroethane, diethyl ether,ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol,isopropanol, tert-butanol, dioxane, pyridine, and the like. Unlessspecified to the contrary, the solvents used in the reactions of thepresent invention are inert solvents.

[0089] A “pharmaceutically acceptable carrier” means a carrier that isuseful in preparing a pharmaceutical composition that is generallycompatible with the other ingredients of the composition, notdeleterious to the recipient, and neither biologically nor otherwiseundesirable, and includes a carrier that is acceptable for veterinaryuse as well as human pharmaceutical use. “A pharmaceutically acceptablecarrier” as used in the specification and claims includes both one andmore than one such carrier.

[0090] A “pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

[0091] (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,2-napthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylicacid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; or

[0092] (2) salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

[0093] “Crystal form” refers to various solid forms of the samecompound, for example polymorphs, solvates, and amorphous forms.

[0094] (a) Polymorphs are crystal structures in which a compound cancrystallize in different crystal packing arrangements, all of which havethe same elemental composition. Different polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate.

[0095] (b) Solvates are generally a crystal form that contains eitherstoichiometric or non-stoichiometric amounts of a solvent. Often, duringthe process of crystallization some compounds have a tendency to trap afixed molar ratio of solvent molecules in the crystalline solid state,thus forming a solvate. When the solvent is water, hydrates may beformed.

[0096] (c) Amorphous forms are noncrystalline materials with no longrange order and generally do not give a distinctive powder X-raydiffraction pattern.

[0097] Crystal forms of the present invention have been obtained for2-[4-(4-isoproxybenzyl)phenyl]amino-imidazoline sulfate, and aredesignated as Crystal Forms I and II. Crystal Forms I and II wereobtained by utilizing the methods described in Examples 1 and 22,respectively, and are described in more detail in Examples 21-23.Crystal forms, in general, are further described in in Byrn et al.,Pharmaceutical Research, 1995, vol 12(7), 945-954, and in Remington: TheScience and Practice of Pharmacy 1995, edited by E. W. Martin, MackPublishing Company, I9th edition, Easton, Pa., Vol. 2, Chapter 83,1447-1462.

[0098] “Treating” or “treatment” of a disease includes:

[0099] (1) preventing the disease, i.e., causing the clinical symptomsof the disease not to develop in a mammal that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease,

[0100] (2) inhibiting the disease, i.e., arresting the development ofthe disease or its clinical symptoms, or

[0101] (3) relieving the disease, i.e., causing regression of thedisease or its clinical symptoms.

[0102] A “therapeutically effective amount” means the amount of acompound that, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease state being treated, the severity of the disease treated,the age and relative health of the subject, the route and form ofadministration, the judgement of the attending medical practitioner, andother factors.

[0103] As is well-known in the art, the imidazolin-2-ylamino group incompounds such as the compounds of Formula I is in tautomericequilibrium with the imidazolin-2-ylideneamino group:

[0104] For convenience, all the compounds of Formula I are shown ashaving the imidazolin-2-yl-amino structure, but it is to be understoodthat compounds of both tautomeric forms are intended to be within thescope of the invention.

[0105] Nomenclature

[0106] The naming and numbering of the compounds of this invention isillustrated below:

[0107] Side chains of the R¹ substituent are numbered as shown below:

[0108] The compounds of the invention are named as imidazolinederivatives, and the nomenclature used in this application is generallybased on the IUPAC recommendations. However, because a strict adherenceto these recommendations would result in the names changingsubstantially when only a single substituent is changed, compounds havebeen named in a form that maintains consistency of nomenclature for thebasic structure of the molecule.

[0109] For example, a compound of Formula I wherein R¹ is a grouprepresented by formula (A), R² and R⁴ are hydrogen, and R³ issec-butoxy, is named 2-[4-(4-sec-butoxybenzyl)phenyl]amino-imidazoline.

[0110] For example, a compound of Formula I wherein R¹ is a grouprepresented by formula (B) in which X is S, R² and R⁴ are hydrogen, andR⁵ is methoxy, is named2-[4-(5-methoxythienyl-2-ylmethyl)phenyl]amino-imidazoline.

[0111] For example, a compound of Formula I wherein R¹ is a grouprepresented by formula (C) in which X is N, R² and R⁴ are hydrogen, andR⁶ is ethylaminocarbonyl, is named2-[4-(1-ethylaminocarbonyl-piperidin-4-ylmethyl)phenyl]amino-imidazoline.

[0112] Preferred Compounds

[0113] Among the family of compounds of the present invention set forthin the Summary of the Invention, a preferred category includes thecompounds of Formula I in which R² and R⁴ are each independently in eachoccurrence hydrogen or halogen; preferably hydrogen, fluoro or chloro.

[0114] Within this category, one preferred subgroup includes thecompounds of Formula I in which R¹ is a group represented by formula (A)wherein:

[0115] (1) R³ is —(CH₂)_(m)OY wherein m is an integer from 0 to 3, and Yis preferably:

[0116] (a) alkyl, preferably methyl, isopropyl, sec-butyl, isobutyl, ortert-butyl;

[0117] (b) alkyloxyalkyl, preferably 2-ethoxy-1-(ethoxymethyl)ethyl;

[0118] (c) cycloalkyl, preferably cyclopentyl or cyclohexyl; or

[0119] (d) heterocyclyl, preferably tetrahydropyran-2-yl ortetrahydropyran-4-yl;

[0120] (2) R³ is —O(CH₂)_(n)Z, wherein n is an integer from 1 to 4, andZ is preferably:

[0121] (a) cycloalkyl, preferably cyclopentyl or cyclohexyl;

[0122] (b) heterocyclyl, preferably tetrahydropyran-2-yl ortetrahydropyran-4-yl; or

[0123] (c) hydroxyalkyl, preferably 1-hydroxymethyl;

[0124] (3) R³ is —(CH₂)_(m)SO₂NR⁸R⁹ or —(CH₂)_(m)CONR⁸R⁹, wherein m isan integer from 0 to 3 and

[0125] (a) R^(a) is hydrogen or alky, preferably hydrogen, methyl,ethyl, or isopropyl;

[0126] (b) R⁹ is

[0127] (i) alkyl, preferably methyl, ethyl, propyl, isopropyl,sec-butyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; or

[0128] (ii) arylalkyl, preferably benzyl; or

[0129] (4) R³ is —(CH₂)_(m)NR⁷SO₂R⁹ or —(CH₂)_(m) NR⁷COR⁹, wherein m isan integer from 0 to 3 and

[0130] (a) R⁷ is hydrogen or alky, preferably hydrogen, methyl, ethyl,or propyl;

[0131] (b) R⁹ is

[0132] (i) alkyl, preferably methyl, ethyl, propyl, or isopropyl;

[0133] (ii) aryl, preferably phenyl; or

[0134] (iii) arylalkyl, preferably benzyl.

[0135] Within this category, another preferred subgroup includes thecompounds of Formula I in which R¹ is a group represented by formula (B)wherein X is S: and

[0136] (1) R³ is —(CH₂)_(m)OY, preferably wherein m is an integer from 0or 1, and Y is:

[0137] (a) alkyl, preferably methyl, isopropyl, isobutyl, sec-butyl ortert-butyl;

[0138] (b) alkyloxyalkyl, preferably 2-ethoxy-1-(ethoxymethyl)ethyl;

[0139] (c) cycloalkyl, preferably cyclopentyl or cyclohexyl; or

[0140] (d) heterocyclyl, preferably tetrahydropyran-2-yl ortetrahydropyran-4-yl; or

[0141] (2) R³ is —O(CH₂)_(n)Z, wherein n is an integer from 1 to 4, andZ.

[0142] Within this category, another preferred subgroup includes thecompounds of Formula I in which R¹ is a group represented by formula (C)wherein X is N.

[0143] Exemplary particularly preferred compounds are:

[0144] 2-[4-(4-isoproxybenzyl)phenyl]amino-imidazoline;

[0145] 2-{4-[4-(sec-butoxy)benzyl]phenyl}amino-imidazoline;

[0146] 2-{4-[4-(cyclopentyloxy)benzyl]phenyl}amino-imidazoline;

[0147] 2-{4-[4-(tetrahydropyran-4-yloxy)benzyl]phenyl)amino-imidazoline;

[0148]2-{4-[4-(tetrahydropyran-4-ylmethoxy)benzyl]phenyl}amino-imidazoline;

[0149]2-{4-[4-(tetrahydropyran-2-ylmethoxy)benzyl]phenyl}amino-imidazoline;

[0150]2-{4-[2-fluoro-4-(tetrahydropyran-4-ylmethoxy)benzyl]phenyl)amino-imidazoline;

[0151]2-{4-[4-(2-ethoxy-1-(ethoxymethyl)ethoxy)benzyl]phenyl}amino-imidazoline;

[0152]2-[4-(4-cyclopentyloxythienyl-2-ylmethyl)phenyl]amino-imidazoline;

[0153]2-[4-[4-(4-methoxyphenyl)sulfonylmethylamino-ethoxybenzyl]phenyl)amino-imidazoline;

[0154] 2-{4-[4-(1-hydroxymethyl-ethoxy)benzyl]phenyl}amino-imidazoline;

[0155] 2-[4-(5-methoxythienyl-2-ylmethyl)phenyl]amino-imidazoline;

[0156] 2-[4-(4-butylaminosulfonylbenzyl)phenyl]amino-imidazoline;

[0157] 2-[4-(4-isoproxymethylbenzyl)phenyl]amino-imidazoline;

[0158] 2-[4-(4-secbutoxymethylbenzyl)phenyl]amino-imidazoline;

[0159] 2-{4-[4-(isobutylaminosulfonyl)benzyl}phenyl}amino-imidazoline;

[0160] 2-[4-(4-benzylaminocarbonylbenzyl)phenyl]amino-imidazoline;

[0161] 2-[4-(4-isopropylaminosulfonylbenzyl)phenyl]amino-imidazoline;

[0162] 2-[4-(4-isobutylaminocarbonylbenzyl)phenyl]amino-imidazoline; and

[0163] 2-[4-(4-tert-butylaminosulfonylbenzyl)phenyl]amino-imidazoline.

General Synthetic Scheme

[0164] Compounds of this invention can be made by the methods depictedin the reaction schemes shown below.

[0165] The starting materials and reagents used in preparing thesecompounds are either available from commercial suppliers such as AldrichChemical Co., or are prepared by methods known to those skilled in theart following procedures set forth in references such as Fieser andFieser's Reagents for Organic Synthesis, Wiley & Sons: New York, 1991,Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier SciencePublishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions,Wiley & Sons: New York, 1991, Volumes 1-40. These schemes are merelyillustrative of some methods by which the compounds of this inventioncan be synthesized, and various modifications to these schemes can bemade and will be suggested to one skilled in the art having referred tothis disclosure.

[0166] The starting materials and the intermediates of the reaction maybe isolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystalllization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

[0167] Unless specified to the contrary, the reactions described hereintake place at atmospheric pressure over a temperature range from about−78° C. to about 150° C., more preferably from about 0° C. to about 125°C., and most preferably at about room (or ambient) temperature, e.g.,about 20° C.

[0168] In general, the compounds of Formula I are prepared by reactingintermediate phenylamine compounds of Ia to Il with an imidazolinecompound 40 as an acid addition salt or a free base. Schemes A to Gdescribe methods to prepare intermediate phenylamine compounds where R¹is a group represented by formula (A); Schemes H to I describe methodsto prepare intermediate phenylamine compounds where R¹ is a grouprepresented by formula (B); and Schemes J to L describe methods toprepare intermediate phenylamine compounds where R¹ is a grouprepresented by formula (C). Scheme M describes a method to preparecompounds of Formula I.

Scheme A

[0169] Scheme A describes a method of preparing compounds of Formula Iwherein R¹ is a group represented by formula (A) and R³ is —O(CH₂)_(n)Zor —(CH₂)_(m)OY, from the corresponding intermediate compound of formulaIa.

[0170] In general, the starting compounds of formula 1a, 1b, 1c, 2a, 2c,and 3a are commercially available, for example from Aldrich ChemicalCompany, or are known to or can readily be synthesized by those ofordinary skill in the art. For example, a methoxybenzoyl-nitrobenzene 3acan be prepared by the method described in Shani, Jashovam et al., J.Med. Chem., 1985, 28, 1504.

[0171] Route (a) describes a preparation of a compound of formula Iawhere R³ is defined as above, in particular where m is an integer 0.

[0172] In step 1, a methoxybenzoyl-nitrobenzene 3a is prepared byacylating a methoxybenzene 1a with an acylating agent 2a where L is aleaving group such as chloro, under Friedel-Crafts acylating conditions.The reaction is carried out under an inert atmosphere in the presence ofa Lewis acid such as aluminum chloride or boron trifluoride, and thelike. Suitable inert organic solvents for the reaction includehalogenated hydrocarbons, such as dichloromethane, dichloroethane,carbon disulfide, and the like, preferably carbon disulfide.

[0173] In step 2, a hydroxybenzoyl-nitrobenzene 4a is prepared bytreating compound 3a with a strong acid such as a mixture of hydrobromicacid in glacial acetic acid. The demethylation reaction proceeds uponheating at a high temperature or at reflux temperature.

[0174] In step 3, a compound 5a is prepared by the direct alkylation ofcompound 4a with an alkylating agent such as an alkyl halide or with anacylating agent such as a halocarboxylic acid ester. The reactionproceeds under an inert atmosphere in the presence of an iodide catalystsuch as sodium or potassium iodide, and a base such as potassiumcarbonate, sodium carbonate or cesium carbonate. Suitable solvents forthe reaction include aprotic organic solvents, for example acetone,acetonitrile, N,N-dimethylformamide, N-methyl pyrrolidone,tetrahydrofuran, and the like, preferably tetrahydrofuran.

[0175] Alternatively, the compound 5a is prepared by reacting compound4a with an organic phosphine such as triphenylphosphine in combinationwith a dialkyl azodicarboxylate such as diethyl azodicarboxyate underMitsunobu reaction conditions. Suitable solvents for the reactioninclude inert organic solvents such as N,N-dimethylformamide,N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, and the like,preferably tetrahydrofuran.

[0176] In step 4, a phenylamine compound of formula Ia is prepared bythe reducing the keto group and nitro group of compound 5a. Suitableketo and nitro group reducing conditions include nickel boride in acidicmethanol or catalytic hydrogenation using a platinum or palladiumcatalyst (e.g., PtO₂ or Pd/C, preferably 10% Pd/C) in a protic organicsolvent such as acidic methanol or acidic ethanol, preferably acidicethanol.

[0177] Route (b) describes an alternative preparation of a compound offormula Ia where R³ is as defined above, in particular where m is aninteger 0.

[0178] In step 1, a substituted-bromobenzene 2b is prepared by treatinga bromophenol 1b with an alkylating agent such as an alkyl halide. Thereaction proceeds in the presence of a base such as potassium carbonate,sodium carbonate or cesium carbonate, and a catalyst such as sodiumiodide. Suitable solvents for the reaction include aprotic solvents suchas N,N-dimethylformamide, tetrahydrofuran, acetonitrile, and the like.

[0179] In step 2, a organometallic compound 3b where M Br is anorganometallic reagent, can be readily synthesized by those of ordinaryskill in the art, for example by treating compound 2b with a suitablemetal under Grignard reaction conditions. The reaction proceeds under aninert atmosphere in an aprotic organic solvent such as tetrahydrofuran.

[0180] In step 3, a benzoyl-nitrobenzene 5b is prepared by reactingcompound 3b with an acylating agent such as an acyl halide where L is aleaving group such as chloro, in the presence of a catalyst such astetrakis(triphenylphosphine)palladium. The reaction proceeds under aninert atmosphere in an aprotic organic solvent such as tetrahydrofuran.

[0181] A phenylamine compound of formula Ia is subsequently prepared byutilizing the methods described above in Scheme A, route (a), step 4.

[0182] Route (c) describes an alternative preparation of a compound offormula Ia where R³ is as defined above, in particular where m is aninteger 1.

[0183] A benzyl bromide 1d is prepared by reacting a bromobenzyl bromide1c with a desired alcohol in the presence of a strong base such assodium hydride. The reaction proceeds under an inert atmosphere in anaprotic solvent such as N,N-dimethylformamide, tetrahydrofuran,acetonitrile, and the like.

[0184] An amino-protected chlorobenzyl-phenylamine 2d where P is anamino-protecting group, is prepared by reacting a chlorobenzylisocyanate 2c with an amino-protecting reagent such as atrialkylsilyethyl alcohol. The reaction proceeds under an inertatmosphere in an aprotic solvent such as N,N-dimethylformamide,tetrahydrofuran, acetonitrile, and the like.

[0185] In step 1, an amino-protected benzylphenyl 3d is prepared bycoupling compound 1d and compound 2d under Stille reaction conditions.For example, the reaction proceeds in the presence of lithiatedcompounds such as tert-butyllithium; tin compounds such as tributyltinhalide; and a catalyst such as tetrakis(triphenylphosphine)palladium.The reaction proceeds under an inert atmosphere in an aprotic solventsuch as hexamethylphosphoramide, N,N-dimethylformamide, tetrahydrofuran,acetonitrile, dimethyl sulfoxide, and the like.

[0186] In step 2, a phenylamine compound of formula Ia is prepared byremoving the amino-protecting group from compound 3d by treatment with aspecific cleaving reagent, for example tetra-n-butylammonium fluoride.The reaction proceeds under an inert atmosphere in an aprotic solventsuch as N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dimethylsulfoxide, and the like.

[0187] Exemplary preparations of compounds of Formula I by this methodfrom the corresponding compounds of formula Ia are described in detailin Examples 1-4. Exemplary preparations of compounds of formula 1d and2d are described in detail in Preparations 1 and 2, respectively.

Scheme B

[0188] Scheme B describes an alternative method of preparing compoundsof Formula I where R¹ is a group represented by formula (A) and R³ isalkyl, cycloalkyl, halo, heterocyclyl, or —NR⁸R⁹, from the correspondingintermediate compound of formula Ib.

[0189] In general, the starting compounds 1e 2e, 1f, and 2f arecommercially available, for example from Aldrich Chemical Company, orare known to or can readily be synthesized by those of ordinary skill inthe art.

[0190] Route (a) describes a preparation of a compound of formula Ibwhere R³ is as defined above starting from a fluorobenzene 1e.

[0191] In step 1, a fluorobenzoyl-nitrobenzene 3e is prepared byacylating a fluorobenzene 1e with an acylating agent 2e where L is aleaving group such as chloro. Suitable solvents for the reaction includehalogenated hydrocarbons, such as dichloromethane, dichloroethane,carbon disulfide, and the like, preferably carbon disulfide.

[0192] In step 2, an R³-substituted-benzoyl-nitrobenzene 6 is preparedby the displacement of the fluoro group of the compound of formula 3e bya primary or secondary amine, such as dimethylamine, morpholine, and thelike. The reaction is carried out in the presence of a base, e.g.,potassium carbonate, sodium carbonate, cesium carbonate, and the like,in an aprotic organic solvent such as tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, and the like, preferablydimethyl sulfoxide.

[0193] In step 3, a phenylamine compound of formula Ib is prepared bythe reduction of the keto group and nitro group of the compound offormula 6, utilizing the reaction conditions described in Scheme A,route (a), step 4.

[0194] Route (b) describes an alternative preparation of a compound offormula Ib, in particular where R³ is alkyl or cycloalkyl.

[0195] In step 1, an alkylbenzoyl-nitrobenzene 6 is prepared by reactingalkylbenzene 1f with an acylating agent 2f where L is a leaving groupsuch as chloro, under Friedel-Crafts acylating conditions. The reactionis carried out in the presence of a Lewis acid such as aluminum chlorideor boron trifluoride, and the like. Suitable solvents for the reactioninclude halogenated hydrocarbons such as dichloromethane,dichloroethane, carbon disulfide, and the like, preferably carbondisulfide.

[0196] In step 2, a phenylamine compound of formula Ib is prepared bythe reduction of the keto group and nitro group of the compound offormula 6, utilizing the reaction conditions described in Scheme A,route (a), step 4.

[0197] An exemplary preparation of a compound of Formula I by thismethod from the corresponding compound of formula Ib is described indetail in Example 5.

Scheme C

[0198] Scheme C describes an alternative method of preparing compoundsof Formula I where R¹ is a group represented by formula (A) and R³ is—(CH₂)_(m)NR⁷SO₂R⁹, from the corresponding intermediate compounds offormula Ic.

[0199] Route (a) describes the preparation of a compound of formula Icwhere R³ is a sulfonamide group, in particular where m is an integer 1:

[0200] In step 1, a methylbenzoyl-nitrobenzene 3g is prepared byacylating a methylbenzene 1g with an acylating agent 2g where L is aleaving group such as chloro, under Friedel-Crafts acylating conditions.The reaction is carried out under an inert atmosphere in the presence ofa Lewis acid such as aluminum chloride or boron trifluoride, and thelike. Suitable inert organic solvents for the reaction includehalogenated hydrocarbons, such as dichloromethane, dichloroethane,carbon disulfide, and the like, preferably carbon disulfide.

[0201] In step 2, a bromobenzoyl-nitrobenzene 7 is prepared by benzylicbromination of compound of formula 3g with a suitable brominating agentsuch as N-bromosuccinimide. The bromination proceeds upon heating in thepresence of a free radical initiator such as benzoyl peroxide under aninert atmosphere (e.g., argon or nitrogen, preferably argon). Suitablenonpolar solvents for the reaction are chlorinated or aromatichydrocarbons such as carbon tetrachloride or benzene.

[0202] In step 3, a bromobenzyl-nitrobenene 8 is prepared by reductionof the keto group in compound of formula 7 by treatment with a reducingagent selective for the keto group, such as triethylsilane. The reactionproceeds under an inert atmosphere in the presence of a strong acid suchas trifluoromethanesulfonic acid. Suitable solvents for the reactioninclude halogenated hydrocarbons such as dichloromethane ordichloroethane.

[0203] In step 4, an azidobenzyl-nitrobenzene 9 is prepared by thedisplacement of the benzylic bromide of compound 8 with a nucleophilicazide anion. Suitable solvents for the reaction are aprotic organicsolvents such as N,N-dimethylformamide, N-methylpyrrolidone,tetrahydrofuran, and the like.

[0204] In step 5, an aminobenzyl-nitrobenzene 10 is prepared by thereduction of the azide to a primary amine by reacting compound 9 with asuitable azide reducing agent such as triphenylphosphine and water.Suitable solvents for the reaction are organic solvents such as diethylether, 1,4-dioxane, tetrahydrofuran, and the like, preferablytetrahydrofuran.

[0205] In step 6, a sulfonylaminobenzyl-nitrobenzene 11 is prepared byreacting compound 10 with a sulfonylating agent R⁹SO₂L where L is aleaving group, particularly chloro, in the presence of a base, e.g.,triethylamine. Sulfonyl halides are commercial available or may beprepared by methods such as those described in (1) Langer, R. F., Can.J. Chem., 1983, 61, 1583-1592; Aveta, R. et al., Gazetta ChimicaItaliana, 1986, 116, 649-652; or King, J. F. and Hillhouse, J. H., CanJ. Chem., 1976, 54, 498. Suitable solvents for the reaction arehalogenated hydrocarbons such as dichloromethane, or a two-phase systemutilizing water and ethyl acetate (e.g., Schotten-Baumann reactionprocedure).

[0206] In step 7, a phenylamine compound of formula Ic is prepared byreducing the nitro group of compound 11 to an amino group. Suitablenitro reducing agents include nickel boride in acidic methanol orcatalytic hydrogenation using a platinum or palladium catalyst (e.g.,PtO₂ or Pd/C) in an organic solvent such as ethanol or ethyl acetate.

[0207] Alternatively, route (b) describes the preparation of a compoundof formula Ic where R³ is a sulfonamide group, in particular where m isan integer 0:

[0208] A compound of formula Ic′ is prepared by reacting a4,4′-methylenedianiline 12 with a sulfonylating agent such as a sulfonylhalide, and utilizing the reaction conditions described above in step 6,and performing an acid-base extraction with a hydroxide and a mineralacid.

[0209] Optionally, a compound of formula Ic can be prepared by furtheralkylating the compound of formula Ic′ with a suitable alkylating agentin the presence of a strong base such as potassium tert-butoxide.Suitable solvents include aprotic organic solvents such as acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, and the like, preferablydimethyl sulfoxide.

[0210] Exemplary preparations of compounds of Formula I by this methodfrom the corresponding compounds of formulae Ic′ and Ic are described indetail in Examples 6-9.

Scheme D

[0211] Scheme D describes an alternative method of preparing compoundsof Formula I where R¹ is a group represented by formula (A) and R³ is—(CH₂)_(m)NR⁷COR⁹, from the corresponding intermediate compounds offormula Id.

[0212] Route (a) describes the preparation of a compound of formula Idwhere R³ is a carboxamide group, in particular where m is an integer 1:

[0213] In general, a compound of formula Id is prepared by utilizing thereaction conditions previously described in Scheme C, route (a), but instep 6, the aminobenzyl-nitrobenzene 10 is reacted with a acylatingagent R⁹COL where L is a leaving group such as chloro, to give acarboxamide 13. A phenylamine compound of formula Id is then prepared byproceeding correspondingly as in step 7.

[0214] Alternatively, route (b) describes the preparation of a compoundof Formula Id where R³ is a sulfonamide group, in particular where m isan integer 0:

[0215] In general, a compound of formula Id′ is prepared by utilizingthe reaction conditions previously described in Scheme C, route (b), butthe 4,4′-methylenedianiline 12 is reacted with an acylating agent suchas a acyl halide to give a compound of formula Id′. Then optionally, acompound of formula Id can be prepared by further alkylating thecompound of formula Id′ with a suitable alkylating agent in the presenceof a strong base such as potassium tert-butoxide. Suitable solventsinclude aprotic organic solvents such as tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, and the like, preferablydimethyl sulfoxide.

[0216] An exemplary preparation of a compound of Formula I by thismethod from the corresponding compound of formula Id is described inExample 7.

Scheme E

[0217] Scheme E describes an alternative method of preparing compoundsof Formula I where R¹ is a group represented by formula (A) and R³ is—(CH₂)_(m)NR⁷C(V)NR⁸R⁹ where V is S or O, from the correspondingintermediate compounds of formula Ie.

[0218] Route (a) describes the preparation of a compound of formula Iewhere R³ is an urea/thiourea group, in particular where m is an integer1:

[0219] In general, a compound of formula Ie is prepared by utilizing thereaction conditions previously described in Scheme C, route (a), but instep 6, reacting the aminobenzyl-nitrobenzene 10 with anisocyanate/isothiocyanate in an aprotic organic solvent, to give anurea/thiourea compound 14. A phenylamine compound of formula Ie is thenprepared by proceeding correspondingly as in step 7.

[0220] Alternatively, route (b) describes the preparation of a compoundof Formula Ie where R³ is a an urea/thiourea group, in particular wherem is an integer 0:

[0221] In general, a compound of formula Ie′ is prepared by utilizingthe reaction conditions previously described in Scheme C, route (b), butreacting a 4,4′-methylenedianiline 12 with an isocyanate/thioisocyanatein an aprotic organic solvent such as dichloromethane, tetrahydrofuran,N,N-dimethylformamide, and the like. Then optionally, a compound offormula Ie can be prepared by further alkylating the compound of formulaIe′ with a suitable alkylating agent in the presence of a strong basesuch as potassium tert-butoxide. Suitable solvents include aproticorganic solvents such as tetrahydrofuran, dimethyl sulfoxide,N,N-dimethylformamide, and the like, preferably dimethyl sulfoxide.

[0222] Alternatively, route (c) describes the preparation of a compoundof Formula I where R³ is an urea/thiourea group, in particular where mis an integer 0:

[0223] In step 1, a compound 15 where P is an amino-protecting group, isprepared by attaching a suitable amino-protecting group such as benzyl,tertbutoxycarbonyl (BOC) or carbobenzyloxy (CBZ) to compound 12 bymethods known to one of ordinary skill in the art, for example underunder Schotten-Baumann conditions.

[0224] In step 2, an urea/thiourea compound 16 is prepared by reacting acompound 15 with an isocyanate/isothiourea in a organic solventincluding dichloromethane, dicloroethane, or tetrahydrofuran.

[0225] In step 3, a compound of formula Ie is prepared by removing theamino-protecting group from compound 16 under hydrogenation conditionsusing a catalyst such as palladium or platinum catalysts. Suitablesolvents for the reaction include protic or aprotic organic solventssuch as methanol, ethanol, ethyl acetate, and the like.

[0226] An exemplary preparation of a compound of Formula I by thismethod from the corresponding compound of formula Ie is described indetail in Example 10.

Scheme F

[0227] Scheme F describes an alternative method of preparing compoundsof Formula I where R¹ is a group represented by formula (A), and R³ is—(CH₂)_(m)SO₂NR⁸R⁹ from the corresponding intermediate compounds offormula If.

[0228] Route (a) describes the preparation of a compound of Formula Ifwhere R³ is a sulfonamide group, in particular where m is an integer 0:

[0229] In step 1, a chlorosulfonylbenzyl-nitrobenzene 18 is prepared byreacting a benzyl-nitrobenzene 17 with a chlorosulfonating agent suchchlorosulfonic acid. The reaction proceeds at a temperature of about−50° to 10° C. in a inert organic solvent such as dichloromethane ordichloroethane.

[0230] In step 2, an aminosulfonylbenzyl-nitrobenzene 20 is prepared byreacting compound 18 with a primary or secondary amine. Suitablesolvents for the reaction include inert organic solvents such asdicohloromethane, dichloroethane or tetrahydrofuran.

[0231] In step 3, a phenylamine compound of formula It is prepared byreducing the nitro group of compound 37 to an amino group. Suitablenitro group reducing conditions include catalytic hydrogenation using aplatinum or palladium catalyst in a protic organic solvent, such asmethanol, ethanol, or ethyl acetate.

[0232] Route (b) describes an alternative preparation of a compound ofFormula If where R³ is a sulfonamide group, in particular where m is aninteger 1:

[0233] The bromobenzyl-nitrobenzene 7 is prepared as previouslydescribed in Scheme C.

[0234] In alternative step 1a, a compound 19 is prepared by reactingcompound 7 with a sulfurous acid salt such as aqueous sodium sulfite orpotassium sulfite. The reaction proceeds at reflux temperature in wateror an acetonitrile-water mixture.

[0235] In alternative step 1b, the compound 18 is then prepared bytreating compound 19 with a chlorinating agent such as phosphoruspentachloride. The reaction can be performed neat or in the presence ofphosphorus oxychloride.

[0236] The phenylamine compound of formula If is then prepared byproceeding correspondingly as in Scheme F, route (a), steps 2 and 3.

[0237] Exemplary preparation of compounds of Formula I by this methodfrom the corresponding compounds of formula If are described in detailin Examples 11-12.

Scheme G

[0238] Scheme G describes an alternative method of preparing compoundsof Formula I where R¹ is a group represented by formula (A) and R³ is—(CH₂)_(m)CONR⁸R⁹, from the corresponding intermediate compounds offormula Ig.

[0239] In step 1, a benzyl-benzoic acid 22 is prepared by reducing theketone group of benzoyl-benzoic acid 21 with a reducing agent selectivefor the ketone group, such as hydrogenation conditions using a palladiumor platinum catalyst. The reaction proceeds at ambient temperature inthe presence of a strong acid such as perchloric acid. Suitable solventsfor the reaction are protic or aprotic solvents such as methanol,ethanol, ethyl acetate, and the like.

[0240] In step 2, a nitrobenzyl-benzoic acid 23 is prepared by followingthe method described in the chemical literaturen, for example Coon etal., J. Org. Chem. 1973, 38, 4243. Briefly, compound 22 is nitrated bythe formation of nitronium salts such as by reaction withtrifluoromethanesulfonic acid and nitric acid. Suitable solvents for thereaction include inert organic solvents such as halogenatedhydrocarbons, for example dichloromethane or dichloroethane.

[0241] In step 3, nitrobenzyl-benzoyl chloride 24 is prepared bytreating compound 23 with a chlorinating agent such as phosgene orphosgene equivalents, phosphorus oxychloride or oxalyl chloride in thepresence of N,N-dimethylformamide (Vilsmeier reaction conditions).Suitable solvents for the reaction include inert organic solvents suchas halogenated hydrocarbons, for example dichloromethane ordichloroethane.

[0242] In step 4, an aminocarbonylbenzyl-nitrobenzene 25 is prepared byreacting compound 24 with a primary or secondary amine. The reactionproceeds in the presence of a base such as pyridine in an inert organicsolvent such as dichloromethane, dichloroethane or tetrahydrofuran.

[0243] In step 5, a phenylamine compound of formula Ig is prepared byreducing the nitro group of compound 25 to an amino group. Suitablenitro group reducing conditions include hydrogenation with a platinum orpalladium catalyst in an alcoholic solvent such as methanol or ethanol.

[0244] An exemplary preparation of a compound of Formula I by thismethod from the corresponding compound of formula Ig is described indetail in Example 13.

Scheme H

[0245] Scheme H describes an alternative method of preparing compoundsof Formula I where R¹ is a group represented by formula (B) where X isS; and R⁵ is or —O(CH₂)^(n)Z or —(CH₂)_(m)OY, in particular where m isan integer 0, from the corresponding intermediate compounds of formulaIh.

[0246] In step 1, a thienyl compound 27b is prepared by treating thebromothienyl 26a with an alkoxide anion, for example sodium methoxide,in the presence of copper salts such as cuprous iodide. The reactionproceeds under an inert atmosphere in a suitable aprotic organic solventsuch as N,N-dimethylformamide, N-methylpyrrolidine, tetrahydrofuran, andthe like.

[0247] In step 2, an ortho-chlorinated thienyl compound 28 can beprepared by methods in the chemical literature, for example, Stanetty etal., Monatshefte Chemie 1989, 120, 65. Briefly, the compound 27b istreated with a halogenating agent such as sulfuryl chloride under aninert atmosphere. Suitable solvents for the reaction include hexane,dichloromethane or dichloroethane.

[0248] In step 3, a thienylhydroxymethyl-nitrobenzene 29 is prepared bytreating compound 28 with a strong base such as n-butyllithium, followedby a benzaldehyde. The reaction proceeds with cooling under an inertatmosphere. Suitable solvents for the reaction include aprotic organicsolvents such as tetrahydrofuran, or diethyl ether, and the like,preferably tetrahydrofuran.

[0249] In step 4, a thienylmethyl-nitrobenzene compound 30 is preparedby reducing the hydroxymethyl group of the compound 29 with an alkylatedhalosilane such as trimethylsilyl chloride, in the presence of an halidesalt, e.g., sodium iodide. Suitable solvents for the reaction includeaprotic solvents for example acetonitrile, N,N-dimethylformamide, andthe like.

[0250] In step 5, a phenylamine compound of formula Ih is prepared byreducing the nitro group of compound 30 to an amino group. Suitablenitro group reducing conditions include nickel boride in acidicmethanol, tin(II) chloride hydrate in ethanol, or catalytichydrogenation using a platinum or palladium catalyst (e.g., PtO₂ orPd/C) in an organic solvent such as ethanol, isopropanol, or ethylacetate.

[0251] An exemplary preparation of a compound of Formula I by thismethod from the corresponding compound of formula Ih is described indetail in Example 14.

Scheme I

[0252] Scheme I describes an alternative method of preparing compoundsof Formula I where R¹ is a group represented by formula (B) where X isS, and R⁵ is or —O(CH₂)_(n)Z or —(CH₂)_(m)OY, in particular where m isan integer 0, from the corresponding intermediate compound of formulaIi.

[0253] In step 1, a thienyl compound 27b can be prepared by a methoddescribed in the chemical literature, for example M. A. Keeystra et al.,Tetrahedron, 1992, 48, 3633. Briefly, the bromothienyl compound 26b istreated with an alkoxide anion, e.g., methoxide or cyclopentoxide, inthe presence of a strong base such as sodium hydride. The reactionproceeds with heating under an inert atmosphere, followed by theaddition of copper salts such as cuprous bromide or cuprous iodide.Suitable solvents for the reaction include inert organic solvents suchas methanol, ethanol, dioxane or tetrahydrofuran.

[0254] In step 2, an alkylstannane 31 is prepared by the stannylation ofthe compound of formula 27b by treatment with a haloalkylstannane, suchas (tri-n-butyl)tin chloride, in the presence of a lithium reagent,e.g., n-butyllithium. The reaction proceeds under an inert atmosphere inan aprotic organic solvent including tetrahydrofuran or diethyl ether.

[0255] In step 3, a P-protected compound 32 where P is anamino-protecting group, is prepared by reacting compound 31 with anamino-protected benzyl chloride reagent, particularly atrimethylsilylalkyl carbonyl group. The reaction proceeds in thepresence of a suitable catalyst including platinum or palladiumcatalyst, e.g., tetrakis(triphenylphosphine)-palladium in a co-solventsuch as hexamethylphosphoramide.

[0256] In step 4, a phenylamine compound of formula Ii is prepared byremoving the amino-protecting group from compound 32 by treatment with anucleophile such as a fluoride ion source, e.g., (tetra-n-butyl)ammoniumfluoride, in an inert organic solvent including dioxane, tetrahydrofuranor diethyl ether, and the like.

[0257] Alternatively, other phenylamine compounds of formula Ii can beprepared by exchanging the —O(CH₂)_(n)Z or —(CH₂)_(m)OY of formula Iiwhere Y or Z is alkyl or cycloalkyl, with other alkyl groups in thepresence of an acid such as p-toluenesulfonic acid. The reactionproceeds under an inert atmosphere at reflux temperature. Suitablesolvents for the reaction include alcoholic solvents such as methanol,ethanol or isopropanol.

[0258] Exemplary preparations of compounds of Formula I by this methodfrom the corresponding compounds of formula Ii is described in detail inExamples 15-17.

Scheme J

[0259] Scheme J describes an alternative method of preparing compoundsof Formula I where R¹ is a group represented by formula (C) where X isN, and R⁶ is —C(V)NR⁸R⁹ where V is O or S, from the correspondingintermediate compound of formula Ij.

[0260] In step 1, a heterocyclylmethyl-phenylamine 34 is prepared byreducing the aromatic and nitro groups of aheteroarylmethyl-nitrobenzene 33 by catalytic hydrogenation conditions,for example, a platinum or palladium catalyst (e.g., PtO₂ or Pd/C,preferably 10% Pd/C) in a protic organic solvent such as acidic methanolor acidic ethanol, preferably acidic ethanol. The reaction proceeds at atemperature of about 20° to 100° C. at about 20-100 psi pressure.

[0261] In step 2, a phenylamine compound of formula Ij is prepared byreacting compound 34 with an isocyanate/thioisocyanate in an inertorganic solvent such as dichloromethane, diethylamine, ortetrahydrofuran. The reaction proceeds under an inert atmosphere atabout −10° to 30° C.

[0262] An exemplary preparation of a compound of Formula I by thismethod from the corresponding compound of formula Ij is described indetail in Example 18.

Scheme K

[0263] Scheme K describes an alternative method of preparing compoundsof Formula I where R¹ is a group represented by formula (C) where X isN, and R⁶ is —COR⁹ or —SO₂R⁹, from the corresponding intermediatecompound of formula Ik.

[0264] The heterocycylylmethyl-phenylamine 34 is prepared as previouslydescribed in Scheme J.

[0265] In step 1, a P¹-protected compound 35 where P¹ is anamino-protecting group, is prepared by attaching a suitableamino-protecting group to compound 34 such as trifluoroacetyl, benzyl,tert-butoxycarbonyl (BOC) or carbobenzyloxy (CBZ), preferably (BOC) bymethods known to one of ordinary skill in the art. Briefly, compound 34is treated with di-tert-butyl-dicarbonate in an aprotic organic solventsuch as tetrahydrofuran.

[0266] In step 2, a P¹- and P²-protected compound 36 where P² is also anamino-protecting group, is prepared by attaching a suitableamino-protecting group to the phenylamino group such as trifluoroacetyl,benzyl, tert-butoxycarbonyl (BOC) or carbobenzyloxy (CBZ), preferablytrifluoroacetyl, to compound 35 by methods known to one of ordinaryskill in the art. Briefly, compound 35 is treated with trifluoroaceticanhydride in the presence of a base such as triethylamine. The reactionproceeds under an inert atmosphere in an inert organic solvent such asdichloromethane, dichloroethane or tetrahydrofuran, and the like.

[0267] In step 3, a P²-protected compound 37 is prepared by removing theP¹ amino-protecting group from compound 36 by treatment with a strongorganic acid such as trifluoroacetic acid in an inert organic solventsuch as halogenated hydrocarbons, for example dichloromethane ordichloroethane.

[0268] In step 4, a compound 38 is prepared by reacting compound 37 witha sulfonylating agent such as a sulfonyl halide or an acylating agentsuch as an acyl halide. The reaction proceeds under an inert atmospherein the presence of a base, such as triethylamine in a halogenatedorganic solvent such as dichloromethane or dichloroethane.

[0269] In step 5, an phenylamine compound of formula Ik is prepared byremoving the P² amino-protecting group from compound 38 by treatmentwith a with a base such as lithium hydroxide. Suitable solvents for thereaction include alcoholic or protic solvents such as methanol, ethanol,or water.

[0270] An exemplary preparation of a compound of Formula I by thismethod from the corresponding compound of formula Ik is described indetail in Example 19.

Scheme L

[0271] Scheme L describes an alternative method of preparing compoundsof Formula I where R¹ is a group represented by formula (C) where X isN, and R⁶ is —CONR⁸R⁹ or —SO₂NR⁸R⁹, from the corresponding intermediatecompound of formula Il.

[0272] The P²-protected compound 37 is prepared as previously describedin Scheme K.

[0273] A compound 39 is prepared by reacting compound 37 with acarbamoyl halide or sulfamoyl halide. The reaction proceeds under aninert atmosphere in the presence of a base, such as triethylamine in ahalogenated organic solvent such as dichloromethane or dichloroethane.

[0274] In the following step, an phenylamine compound of formula Il isprepared by removing the P²-protecting group from compound 39 bytreatment with a with a base such as lithium hydroxide. Suitablesolvents for the reaction include alcoholic or protic solvents such asmethanol, ethanol, or water.

[0275] An exemplary preparation of a compound of Formula I by thismethod from the corresponding compound of formula Il is described indetail in Example 20.

Scheme M

[0276] Scheme M, in general, describes the preparation of compounds ofFormula I where R¹ and R² are as defined in the Summary of the Inventionfrom the corresponding intermediate compounds of formulae Ia-Il.

[0277] The 2-imidazoline compound of formula 40 is known to or canreadily be synthesized by those of ordinary skill in the art. Forexample, the synthesis of the sulfate salt of formula 40 where L ischloro, is described by A Trani and E. Bellasio, J. Het. Chem., 1974,11, 257.

[0278] In general, the imidazoline compounds of Formula I can beprepared by reacting the corresponding intermediate compounds offormulae Ia-In with a 2-imidazoline compound 40 as an acid addition saltor free base. The reaction proceeds on heating under reflux, andtypically under an inert atmosphere. Suitable solvents for the reactionare inert organic solvents including methanol, ethanol, isopropanol,dichloromethane, acetonitrile, tetrahydrofuran, dioxane, and the like.The choice of solvent will depend upon the utilization of the acidaddition salt or free base.

General Utility

[0279] The IP receptor antagonists such as those described in thisinvention possess both anti-inflammatory and analgesic properties invivo. Accordingly, these compounds are therefore useful asanti-inflammatory and analgesic agents in mammals, especially humans.They find utility in pain conditions (states) from a wide variety ofcauses, including but not limited to, inflammatory pain, surgical pain,visceral pain, dental pain, premenstrual pain, central pain, pain due toburns, migraine or cluster headaches, nerve injury, neuritis,neuralgias, poisoning, ischemic injury, interstitial cystitis, cancerpain, viral, parasitic or bacterial infection, post-traumatic injuries(including fractures and sports injuries), and pain associated withfunctional bowel disorders such as irritable bowel syndrome.

[0280] The compounds also find utility in inflammatory conditions from avariety of causes, including but not limited to, bacterial, fungal orviral infections, rheumatoid arthritis, osteoarthritis, surgery, bladderinfection or idiopathic bladder inflammation, over-use, old age, ornutritional deficiencies, prostatis, conjunctivitis.

[0281] The compounds also find utility in bladder disorders associatedwith bladder outlet obstruction and urinary incontinence conditions suchas-urge incontinence, stress incontinence, and bladder hyperreactivity.

[0282] The compounds also find utility in respiratory conditions such asasthma, in which the C-fibers in the lungs are hyper-responsive to anumber of environmental stimuli, including cold air, dust, pollen andother antigens. Since these C-fibers express IP prostanoid receptors,the activation of these receptors by PGI₂, and a subsequent release ofneurokinins may contribute to the contraction of lung smooth muscletissues, edema, and mucus secretion. Thus, compounds of this inventiongiven either systemically or with aerosol application may constitute aneffective therapy for asthma.

[0283] In addition, the compounds also find utility in the treatment ofseptic shock.

Testing

[0284] The anti-inflammatory/analgesic activity of the compounds of thisinvention may be assayed by in vivo assays such as the RatCarrageenan-Induced Mechanical Hyperalgesia Paw Assay and the RatComplete Freund's Adjuvant-induced Mechanical Hyperalgesia Assay, asdescribed in more detail in Examples 30 and 31, respectively. Activityin the inhibition of contractions may be assayed by in vitro assays suchas the Inhibition of Bladder Contractions Induced by IsovolumetricBladder Distension Assay, as described in more detail in Examples 32 and33. Activity in the inhibition of the septic shock may be assayed by invivo assays such as the Rat Reversal of Endotoxin-Induced HypotensionAssay, as described in more detail in Example 34.

Administration and Pharmaceutical Composition

[0285] The invention includes a pharmaceutical composition comprising acompound of the present invention or a pharmaceutically acceptable saltor a crystal form thereof together with one or more pharmaceuticallyacceptable carriers, and optionally other therapeutic and/orprophylactic ingredients.

[0286] In general, the compounds of this invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this application, to ascertaina therapeutically effective amount of the compounds of this inventionfor a given disease.

[0287] In general, compounds of this invention will be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal orparenteral (including intramuscular, intraarterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is oral using a convenient daily dosage regimen which canbe adjusted according to the degree of affliction.

[0288] The compounds of the invention, together with a conventionaladjuvant, carrier, or diluent, may be placed into the form ofpharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may comprise of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcomposition may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing one (1) milligram of activeingredient or, more broadly, 0.01 to one hundred (100) milligrams, pertablet, are accordingly suitable representative unit dosage forms.

[0289] The compounds of the present invention may be formulated in awide variety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise the compounds of theinvention or its pharmaceutically acceptable salt or a crystal formthereof as the active component. The pharmaceutically acceptablecarriers can be either solid or liquid. Solid form preparations includepowders, tablets, pills, capsules, cachets, suppositories, anddispersible granules. A solid carrier can be one or more substanceswhich may also act as diluents, flavoring agents, solubilizers,lubricants, suspending agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material. In powders, thecarrier is a finely divided solid which is a mixture with the finelydivided active component. In tablets, the active component is mixed withthe carrier having the necessary binding capacity in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably containing from one to about seventy percent of theactive compound. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges canbe as solid forms suitable for oral administration.

[0290] Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions in aqueous propylene glycol solutions or maycontain emulsifying agents such as lecithin, sorbitan monooleate, oracacia. Aqueous solutions can be prepared by dissolving the activecomponent in water and adding suitable colorants, flavors, stabilizingand thickening agents. Aqueous suspensions can be prepared by dispersingthe finely divided active component in water with viscous material, suchas natural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well known suspending agents. Solidform preparations include solutions, suspensions, and emulsions, and maycontain, in addition to the active component, colorants, flavors,stabilizers, buffers, artificial and natural sweeteners, dispersants,thickeners, solubilizing agents, and the like.

[0291] The compounds of the present invention may be formulated forparenteral administration (e.g., by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, for example solutions in aqueous polyethylene glycol. Examplesof oily or nonaqueous carriers, diluents, solvents or vehicles includepropylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil),and injectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0292] The compounds of the present invention may be formulated fortopical administration to the epidermis as ointments, creams or lotions,or as a transdermal patch. Ointments and creams may, for example, beformulated with an aqueous or oily base with the addition of suitablethickening and/or gelling agents. Lotions may be formulated with anaqueous or oily base and will in general also containing one or moreemulsifying agents, stabilizing agents, dispersing agents, suspendingagents, thickening agents, or coloring agents. Formulations suitable fortopical administration in the mouth include lozenges comprising activeagents in a flavored base, usually sucrose and acacia or tragacanth;pastilles comprising the active ingredient in an inert base such asgelatin and glycerin or sucrose and acacia; and mouthwashes comprisingthe active ingredient in a suitable liquid carrier.

[0293] The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

[0294] The compounds of the present invention may be formulated forvaginal administration. Pessaries, tampons, creams, gels, pastes, foamsor sprays containing in addition to the active ingredient such carriersas are known in the art to be appropriate.

[0295] The compounds of the present invention may be formulated fornasal administration. The solutions or suspensions are applied directlyto the nasal cavity by conventional means, for example with a dropper,pipette or spray. The formulations may be provided in a single ormultidose form. In the latter case of a dropper or pipette this may beachieved by the patient administering an appropriate, predeterminedvolume of the solution or suspension. In the case of a spray this may beachieved for example by means of a metering atomizing spray pump.

[0296] The compounds of the present invention may be formulated foraerosol administration, particularly to the respiratory tract andincluding intranasal administration. The compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC) forexample dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

[0297] When desired, formulations can be prepared with enteric coatingsadapted for sustained or controlled release administration of the activeingredient.

[0298] The pharmaceutical preparations are preferably in unit dosageforms. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active component. The unitdosage form can be a packaged preparation, the package containingdiscrete quantities of preparation, such as packeted tablets, capsules,and powders in vials or ampoules. Also, the unit dosage form can be acapsule, tablet, cachet, or lozenge itself, or it can be the appropriatenumber of any of these in packaged form.

[0299] Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described in Examples 24 to 29.

EXAMPLES

[0300] The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Preparation 1 1-Bromo-4-isopropoxymethylbenzene

[0301] 60% Sodium hydride in mineral oil (0.96 g, 24 mmol) was added toa solution of isopropanol (7.59 mL, 36 mmol) in dryN,N-dimethylformamide (30 mL) at 0° to 5° C. under argon atmosphere.After the mixture was stirred for about 25 minutes, 4-bromo-benzylbromide was added and the mixture stirred at 20° C. for an additional 1hour. The solution was partitioned between saturated ammonium chloride(50 mL) and diethyl ether (50 mL). The aqueous phase was extracted withdiethyl ether (3×20 mL), and the combined organic layers were washedwith water, dried (Na₂SO₄), and evaporated in vacuo. The crude productwas filtered over silica gel to give pure1-bromo-4-isopropoxymethylbenzene (2.33 g, 85%) as clear oil.

Preparation 2 4-Chloromethylphenylcarbamic acid 2-trimethylsilanyl ethylester

[0302] To a mixture of 4-chloromethylphenyl isocyanate (1.07 g, 6.4 mM)in tetrahydrofuran (22 ml) was added 2-trimethylsilyl ethanol (0.91 mL,6.4 mmol) at 20-25° C. under argon. The mixture was stirred for 4 hoursat 20-25° C. The solvent was evaporated in vacuo. Saturated sodiumbicarbonate was added and product was extracted with ethyl acetate. Theextract was washed with water, brine, dried (Na₂SO₄), and concentratedto dryness. Purification by flash chromatography on silica, eluting withhexane/ethyl acetate, gave crystalline 4-chloromethyl-phenylcarbamicacid 2-trimethylsilanyl ethyl ester (1.24 g, 68% yield) as a whitesolid; mp 55-56° C.; ¹H NMR 7.38 (d, J=8.6, 2H), 7.32 (d, J=8.6, 2H),6.60 (bs, 1H), 4.55 (S, 2H), 4.26 (m, 2H), 1.05 (m, 2H), 0.06 (s, 9H).

Example 1 2-[4-(4-Isopropoxybenzyl)phenyl]-amino-imidazoline

[0303] The following is a preparation of a compound of Formula I fromthe corresponding compound of formula Ia in which R¹ is a grouprepresented by formula (A), R² and R⁴ are hydrogen, Y is isopropyl, andm is an integer 0.

[0304] Step 1

[0305] The compound of formula 3a was prepared according to theprocedure of Shani, J. et al., J. Med. Chem, 1985, 28, 1504. Thus, amixture of 4-nitrobenzoyl chloride (90 g, 0.48 mol) and anisole (57.24g, 0.53 mol) in carbon disulfide (450 mL) was stirred in a three neckround bottom flask equipped with nitrogen inlet, condenser andmechanical stirrer that was being cooled in an ice bath. Aluminumchloride (84.0 g, 0.63 mol) was added in portions and stirring continuedat ice bath temperature for 30 minutes, then at room temperature for anadditional 1 hour. The reaction mixture was cooled, treated withconcentrated hydrochloric acid (150 mL), diluted with cold water (250mL). The product was collected, filtered, washed, dried, andcrystallized from ethyl acetate to give4-(4-methoxybenzoyl)-nitrobenzene as an off-white solid, m.p. 120-122°C.; Analysis for C₁₄H₁₁NO₄: Calc.: C, 65.3; H, 4.31; N, 5.44; Found: C,65.22; H, 4.16; N, 5.69.

[0306] Step 2

[0307] A solution of 4-(4-methoxybenzoyl)-nitrobenzene (150 g, 0.58mol), glacial acetic acid (500 mL), and hydrobromic acid (48% w/waqueous solution, 400 mL) was heated under reflux for 16 hours. Thereaction mixture was cooled to room temperature and poured onto crushedice. The crude product as filtered, washed several times with water anddried at about 50° C. under high vacuum. Crystallization from ethylacetate/hexanes gave 4-(4-hydroxybenzoyl)-nitrobenzene (114 g, 81%),m.p. 190-193° C.; Analysis for C₁₃H₉NO₄: Calc.: C, 64.20; H, 3.73; N,5.76; Found: C, 63.95; H, 3.65; N, 5.85; MS m/e (%): 243 (M+; 45).

[0308] Step 3

[0309] A reaction mixture containing 4-(4-hydroxybenzoyl)-nitrobenzene(48.63 g, 0.2 mol), 2-bromopropane (98.4 g, 0.8 mol), sodium iodide (1.5g) and anhydrous potassium carbonate (27.6 g, 0.2 mol) inN,N-dimethylformamide (200 mL) was heated at about 60-70° C. undernitrogen for 18 hours. The reaction mixture was concentrated, and theresidue stirred with water and filtered. The crude product was washedseveral times with water and dried to give a cream-colored product (54.8g, 96%), which was then crystallized from ethyl acetate to give4-(4-isopropoxbenzoyl)-nitrobenzene, m.p. 138° C.; Analysis forC₁₆H₁₅NO₄: C, 67.36; H, 5.30; N, 4.91; Found: C, 67.39; H, 5.28; N,5.07.

[0310] Step 4

[0311] A mixture of 4-(4-isopropoxybenzoyl)-nitrobenzene (14.0 g, 49.09mmol) and 10% palladium on carbon (2.0 g) in a solution of ethanol (250mL) and concentrated hydrochloric acid (30 mL) was hydrogenated at 50psi in a Parr apparatus for 16 hours. The catalyst was removed byfiltration through a Celite pad, and filtrate was concentrated in vacuo.The residue was diluted with ice cold water, basified with concentratedammonium hydroxide solution, and extracted into ethyl acetate. Theorganic extracts were washed with water and brine, and dried (MgSO₄).Removal of the solvent gave a thick oil which on crystallization fromethyl acetate/hexanes gave 4-(4-isopropoxybenzyl)-phenylamine (10.4 g,87%) as a white solid, m.p. 92-93° C.; Analysis for C₁₆H₁₉NO: Calc.: C,79.63; H, 7.94; N, 5.80; Found: C, 79.51; H, 7.92; N, 5.96. MS m/e (%):241 (M+, 83).

[0312] Last Step

[0313] 2-Chloro-2-imidazoline sulfate was prepared according to theprocedures described in A. Trani and E. Bellasio., J. Het. Chem., 1974,11, 257.

[0314] A mixture of 2-chloro-2-imidazoline sulfate (24.36 g, 120 mmol)and 4-(4-isopropoxybenzyl)-phenylamine (24.1 g, 100 mmol) in isopropanol(300 mL) was heated under reflux for 1-2 hours under an inertatmosphere. The reaction mixture was concentrated in vacuo and theresidue diluted with ice cold water. The mixture was basified with 10%sodium hydroxide and thoroughly extracted with dichloromethane. Thecombined organic extracts were washed with cold water and brine, dried(K₂CO₃), and concentrated. Crystallization from diethylether/hexanesgave 2-[4-(4-isopropoxybenzyl)phenyl]-amino-imidazoline (9.94 g, 96%) asan off-white solid, m.p. 103-104° C.; Analysis for C₁₉H₂₂N₃O: C, 73.76;H, 7.49; N, 13.58; Found. C, 73.51; H, 7.42; N, 13.57; MS m/e (%): 309(M+; 100).

[0315] A solution of sulfuric acid (0.08 g) in acetone (1 mL) was addedto a mixture of 2-[4-(4-isopropoxybenzyl)phenyl]-amino-imidazoline (0.5g) in acetone (14 mL). The mixture was warmed, stirred for 15 minutes,and filtered to give 2-[4-(4-isopropoxybenzyl)-phenyl]amino-imidazolinesulfate (0.56 g) as a white solid, m.p. 215-216° C.; Analysis forC₃₈H₄₈N₆O₆S: C, 63.66; H, 6.75; N, 11.72; Found; C 63.50; H, 6.64; N,11.72.

[0316] Proceeding as in Example 1, step 1, and proceeding directly toExample 1, step 0.4 and last step, gave2-[4-(4-methoxybenzyl)phenyl]amino-imidazoline, m.p. 114-116° C.

[0317] Proceeding as in Example 1, step 1, but replacing 4-nitrobenzoylchloride with 3-methoxy-4-nitrobenzoyl chloride and proceeding directlyto Example 1, step 4 and last step, gave2-[4-(4-methoxybenzyl)-3-methoxyphenyl]amino-imidazoline, m.p. 127-128°C.

[0318] Proceeding as in Example 1, step 3, but replacing 2-bromopropanewith ethyl 2-bromopropionate, and then correspondingly as in Example 1,subsequent steps, gave2-{4-[4-(4,5-dihydro-H-imidazol-2-ylamino)benzyl]phenoxy}-propionicacid, m.p. >300° C.; Analysis for C₁₉H₂₁N₃O₃: Calc.: C, 67.24; H 6.24,N, 12.38; Found: C, 66.90; H 6.23, N, 12.31.

[0319] Proceeding as in Example 1, step 3, but replacing 2-bromopropanewith other alkyl halides, and then correspondingly as in Example 1,subsequent steps, the following compounds of Formula I were prepared:

[0320] 2-[4-(4-ethoxybenzyl)phenyl]amino-imidazoline, m.p. 152-153° C.;

[0321] 2-(4-[4-(2,2,2-trifluoroethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 75-78° C.;

[0322] 2-[4-(4-propoxybenzyl)phenyl]amino-imidazoline oxalate, m.p.146-147° C.;

[0323] 2-[4-(4-butoxybenzyl)phenyl]amino-imidazoline hydrochloride, m.p.97-100° C.;

[0324] 2-[4-(4-butoxybenzyl)phenyl]amino-imidazoline oxalate, m.p.172-174° C.;

[0325] 2-[4-(4-isobutoxybenzyl)phenyl]amino-imidazoline hydrochloride,m.p. 127-129° C.;

[0326] 2-[4-(4-pentyloxybenzyl)phenyl]amino-imidazoline oxalate, m.p.163-166° C.;

[0327] 2-{4-[4-(1-methylbutoxy)benzyl]phenyl}amino-imidazoline, m.p.99-112° C.;

[0328] 2-{4-[4-(2-hydroxypropoxy)benzyl]phenyl)amino-imidazolinehydrochloride, m.p. 129-133° C.;

[0329]2-{4-[4-(3-hydroxy-2-hydroxymethylpropoxy)benzyl]phenyl}amino-imidazolinemaleate, m.p. 70-75° C.;

[0330] 2-[4-(4-benzyloxybenzyl)phenyl]amino-imidazoline hydrochloride,Analysis for C₂₃H₂₄N₃OCl: Calc.: C, 70.13; H 6.14, N, 10.67; Found: C,69.79; H 6.10, N, 10.74;2-[4-(4-cyclopentyloxybenzyl)phenyl]amino-imidazoline hydrochloride,m.p. 116-119° C.;

[0331] 2-[4-(4-cyclohexoxybenzyl)phenyl]amino-imidazoline hydrochloride,m.p. 108-110° C.;

[0332] 2-[4-(4-cyclohexylmethoxybenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 95-100° C.;

[0333] 2-[4-(4-tetrahydropyran-2-yloxybenzyl)phenyl]amino-imidazolineoxalate, m.p. 168-170° C.;

[0334] 2-{4-[2-(4-methoxyphenyl)ethoxybenzyl]phenyl}amino-imidazoline,m.p. 122-124° C.;

[0335] 2-[4-(4-benzoylmethoxybenzyl)phenyl]amino-imidazolinehydrochloride, Analysis for C₂₄H₂₄N₃O₂Cl: Calc.: C, 67.28; H 5.86, N,9.81; Found: C, 67.27; H 5.76, N, 9.62;

[0336]2-{4-[4-(cyclopentylaminocarbonyl)methoxybenzyl]phenyl}amino-imidazolinehydrochloride, m.p. 78-81° C.;

[0337]2-(4-[4-(1-piperidinecarbonyl)methoxybenzyl]phenyl}amino-imidazolinehydrochloride, m.p. 65-67° C.;

[0338]2-{4-[4-(phenylaminocarbonyl)methoxybenzyl]phenyl}amino-imidazolinehydrochloride, m.p. 186-187° C.;

[0339]2-{4-[4-(diisopropylaminocarbonyl)methoxybenzyl]phenyl}amino-imidazolinehydrochloride, m.p. 62-65° C.;

[0340]2-{4-[4-(diethylaminocarbonyl)methoxybenzyl]phenyl}amino-imidazolinehydrochloride, Analysis for C₂₂H₂₉N₄O₂Cl: Calc.: C, 60.75; H 7.18, N,12.88; Found: C, 60.91.; H 7.04, N, 12.95;

[0341]2-{4-[4-(isopropylaminocarbonyl)methoxybenzyl]phenyl}amino-imidazolinehydrochloride, m.p. 66-78° C.;

[0342]2-{(4-[4-(N-isopropyl-N-methylaminocarbonyl)methoxybenzyl]phenyl}amino-imidazolinehydrochloride, m.p. 77-81° C.;

[0343]2-{4-[4-(4-methoxyphenyl)aminocarbonylmethoxybenzyl]phenyl}amino-imidazolinehydrochloride, Analysis for C₂₅H₂₇N₄O₃Cl: Calc.: C, 63.33; H 5.91, N,11.82; Found: C, 63.34; H 5.78, N, 11.67;

[0344] 2-[4-(2-fluoro-4-propoxylbenzyl)phenyl]amino-imidazoline oxalate,m.p. 130-133° C.;

[0345] 2-[4-(3-fluoro-4-isopropoxylbenzyl)phenyl]amino-imidazolineoxalate, m.p. 120-121° C.;

[0346]2-[4-(2-fluoro-4-tetrahydropyran-2-ylmethoxybenzyl)phenyl]amino-imidazolinemaleate, m.p. 138-141° C.;

[0347] 2-[4-(3-chloro-4-isopropoxybenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 118-120° C.;

[0348] 2-[4-(2-fluoro-4-methoxybenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 126-129° C.;

[0349] 2-[4-(3-fluoro-4-methoxybenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 138-140° C.;

[0350] 2-[4-(4-fluoro-2-methoxybenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 230-233° C.;

[0351] 2-[4-(2,4-dimethoxybenzyl)phenyl]amino-imidazoline hydrochloride,m.p. 137-143° C.;

[0352] 2-[4-(3,4-dimethoxybenzyl)phenyl]amino-imidazoline hydrochloride,m.p. 127-128° C.; and

[0353] 2-[4-(3-chloro-4-methoxybenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 169-172° C.

Example 22-[4-(4-Tetrahydropyran-4-yloxybenzyl)phenyl]-amino-imidazoline

[0354] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ia in which R¹ is agroup represented by formula (A), R² and R⁴ are hydrogen, Z is4-tetrahydropyran-4-yl, and n is an integer 0.

[0355] 2-[4-(4-Tetrahydropyran-4-yloxybenzyl)phenyl]-amino-imidazolinewas prepared by proceeding as in Example 1, steps 1 and 2, and then toAlternative Step 3:

[0356] Diethyl azodicarboxylate (1.47 g, 8.4 mmol) was slowly addeddropwise to a solution of 4-(4-hydroxybenzoyl)-nitrobenzene (1.7 g, 7mmol) (prepared as described in Example 1, steps),4-hydroxytetrahydropyran (0.78 g, 7.7 mmol) and triphenylphosphine (2.2g, 8.4 mmol) in dry tetrahydrofuran (20 mL) while stirring at roomtemperature under inert atmosphere. The reaction mixture was stirred forah additional hour then quenched with water (1 mL) and concentrated invacuo. The residue was diluted with water and extracted with ethylacetate. The combined organic extracts were washed with water and brine,dried (Na₂SO₄), and concentrated in vacuo. The crude product waschromatographed on silica gel (25% ethyl acetate/hexanes) andcrystallized from hexanes to give4-(4-tetrahydropyran-4-yloxybenzoyl)-nitrobenzene (1.4 g, 61%) as awhite solid, m.p. 105-106° C.; Analysis for C₁₈H₁₇NO₅: Calc.: C, 66.05;H, 5.23; N, 4.28; Found: C, 65.95; H, 5.14; N, 4.38. MS m/e (%): 283(M+; 100).

[0357] Proceeding as in Example 1, steps 4 and last step, but replacing4-(4-isopropoxybenzoyl)-nitrobenzene with4-(4-tetrahydropyran-4-yloxybenzoyl)-nitrobenzene, gave2-[4-(4-tetrahydropyran-4-yloxybenzyl)phenyl]amino-imidazoline, m.p.169-170° C.

[0358] Proceeding as in Example 2, but replacing4-hydroxytetrahydropyran in with other hydroxy compounds, the followingcompounds of Formula I were prepared:

[0359] 2-{4-[4-(1-ethylpropoxy)benzyl]phenyl}amino-imidazoline, Analysisfor C₂₁H₂₇N₃O: Calc.: C, 74.74; H 8.06, N, 12.45; Found: C, 74.62; H7.90, N, 12.33;

[0360] 2-(4-[4-(sec-butoxy)benzyl]phenyl)amino-imidazolinehydrochloride, m.p. 118-119° C.;

[0361] (R)-2-{4-[4-(sec-butoxy)benzyl]phenyl}amino-imidazoline maleate,m.p. 163-164° C.;

[0362] (S)-2-{4-[4-(sec-butoxy)benzyl]phenyl}amino-imidazoline maleate,m.p. 163° C.;

[0363] (S)-2-{4-[4-(2-methylbutoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 119-122° C.;

[0364] 2-[4-(4-hexyloxybenzyl)phenyl]amino-imidazoline oxalate, m.p.150-161° C.;

[0365] 2-{4-[4-(2-methoxyethoxy)benzyl]phenyl}amino-imidazoline, m.p.110-112° C.;

[0366] 2-[4-(4-hydroxybenzyl)phenyl]amino-imidazoline, m.p. 170-177° C.;

[0367] 2-{4-[4-(2-hydroxyethoxy)benzyl]phenyl}amino-imidazoline, m.p.164-165° C.;

[0368] 2-{4-[4-(3-ethoxypropoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 91-92° C.;

[0369] 2-[4-(4-chlorobutoxy)benzyl]phenyl)amino-imidazoline, Analysisfor C₂₀H₂₄N₃₀OCl: Calc.: C, 67.12; H 6.76, N, 11.74; Found: C, 66.84; H6.79, N, 11.80;

[0370] 2-{4-[4-(2-methoxy-1-methylethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 71-74° C.;

[0371] 2-{4-[4-(3-methoxybutoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 71-76° C.;

[0372] 2-{4-[4-(1-hydroxymethylethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m/s 326 (M+1);

[0373]2-{4-[4-(2-hydroxy-1-hydroxymethylethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 50-55° C.;

[0374]2-{4-[4-(2-ethoxy-1-ethoxymethyl)ethoxybenzyl]phenyl}amino-imidazolinehydrochloride, gum;

[0375] 2-{4-[4-(2,3-dihydroxypropoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 55-60° C.;

[0376] 2-{4-[4-(2-phenylethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, Analysis for C₂₄H₂₆N₃OCl: Calc.: C, 70.66; H 6.42, N,10.30; Found: C, 70.42; H 6.37, N, 10.42.;

[0377] 2-{4-[4-(2-phenoxyethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 140-141° C.;

[0378] 2-{4-[4-(3-phenylpropoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 101-104° C.;

[0379] 2-[4-(4-cyclopropylmethoxybenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 121-122° C.;

[0380] 2-[4-(4-cyclobutylmethoxybenzyl)phenyl]amino-imidazoline,Analysis for C₂₁H₂₅N₃O: Calc.: C, 75.19; H 7.51, N, 12.53; Found: C,74.69; H 7.32, N, 11.96;

[0381] 2-{4-[4-(2-cyclopentylethoxy)benzyl]phenyl}amino-imidazolineoxalate, m.p. 152-153° C.;

[0382] 2-{4-[4-(2-cyclohexylethoxy)benzyl]phenyl}amino-imidazolinemaleate, m.p. 144-147° C.;

[0383] 2-{4-[4-(2-cyclohexyloxyethoxy)benzyl]phenyl}amino-imidazolineoxalate, m.p. 120-127° C.;

[0384] 2-{4-[4-(2-isopropoxyethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 76-80° C.;

[0385]2-{4-[4-(2-(2-oxo-pyrrolidin-1-yl)ethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 143-145° C.;

[0386]2-{4-[4-(2-(2-oxo-imidazolin-1-yl)ethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 85-88° C.;

[0387]2-[4-(4-tetrahydropyran-4-ylmethoxybenzyl)phenyl]amino-imidazoline, m.p.159-160° C.;

[0388]2-[4-(4-tetrahydrofuran-3-ylmethoxybenzyl)phenyl]amino-imidazoline, m.p.147-149° C.;

[0389] 2-[4-(4-tetrahydrofuran-3-yloxybenzyl)phenyl]amino-imidazoline,m.p. 149-150° C.;

[0390] 2-{4-[4-(4-methylcyclohexyloxy)benzyl]phenyl}amino-imidazoline,m.p. 80-85° C.;

[0391]2-{4-[4-(5-methyl-[1,3]dioxan-5-ylmethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 85-90° C.;

[0392]2-{4-[4-(3-chloro-2-hydroxymethyl-2-methylpropoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 65-70° C.;

[0393] 2-{4-[4-(2-thien-2-ylethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, Analysis for C₂₂H₂₄N₃OClS: Calc.: C, 63.83; H 5.84, N,10.15; Found: C, 63.85; H 5.80, N, 10.14;

[0394] 2-{4-[4-(2-thien-3-ylethoxy)benzyl)phenyl]amino-imidazolinehydrochloride, Analysis for C₂₂H₂₄N₃OClS: Calc.: C, 63.14; H 5.90, N,10.04; Found: C, 63.30; H 5.81, N, 10.11;

[0395] 2-{4-[4-(2-methanesulfonylethoxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 172-175° C.;

[0396]2-{4-[4-(4-methoxyphenyl)sulfonylaminoethoxybenzyl]phenyl}amino-imidazolinehydrochloride, Analysis for C₂₆H₃₁N₄O₆ClS: Calc.: C, 58.08; H 5.95, N,10.41; Found: C, 57.97; H 9.94, N, 10.58;

[0397] 2-[4-(3-fluoro-4-isobutoxybenzyl)phenyl]amino-imidazolineoxalate, m.p. 134-135° C.;

[0398] 2-[4-(2-fluoro-4-isobutoxybenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 134-135° C.;

[0399]2-{4-[3-fluoro-4-(tetrahydropyran-4-yloxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 149-151° C.;

[0400]2-{4-[2-fluoro-4-(tetrahydropyran-4-yloxy)benzyl]phenyl}amino-imidazoline,m.p. 169-170° C.;

[0401]2-{4-[4-(tetrahydropyran-4-ylmethoxy)benzyl]phenyl}amino-imidazoline,m.p. 124-127° C.;

[0402]2-{4-[3-fluoro-4-(tetrahydropyran-4-ylmethoxy)benzyl]phenyl}amino-imidazoline,m.p. 154-155° C.;

[0403]2-{4-[2-fluoro-(4-tetrahydropyran-4-ylmethoxy)benzyl]phenyl}amino-imidazolinemaleate, m.p. 134-135° C.;

[0404] 2-{4-[2-fluoro-4-pentyloxybenzyl]phenyl}amino-imidazolinehydrochloride, m.p. shrinks at 72° C.;

[0405] 2-{4-[4-(2-isopropoxyethoxy)benzyl]phenyl}amino-imidazolineoxalate, m.p. 134-137° C.;

[0406] 2-[4-(3-chloro-4-isobutoxybenzyl)phenyl]amino-imidazoline, m.p.126-128° C.; and

[0407]2-{4-[3-chloro-4-(tetrahydropyran-4-yloxy)benzyl]phenyl}amino-imidazolinehydrochloride, m.p. 128-130° C.

Example 3 2-[4-(4-Isopropoxybenzyl)phenyl]-amino-imidazoline

[0408] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ia in which R¹ is agroup represented by formula (A), R² and R⁴ are hydrogen, Y isisopropoxy, and m is an integer 0.

[0409] Step 1

[0410] A mixture of 4-bromophenol (30.0 g, 173 mmol), potassiumcarbonate (26.3 g, 190 mol), sodium iodide (0.60 g, 4 mmol),2-bromopropane (85.1 g, 0.692 mmol), and N,N-dimethylformamide (173 mL)was warmed at 60° C. for 17 hours. The solution was cooled to roomtemperature and water (300 mL) was added. The solution was extractedwith diethyl ether. The extract was washed with aqueous sodiumhydroxide, water, and aqueous sodium chloride, dried (Na₂SO₄), filtered,and concentrated. The product was purified by vacuum distillation togive 4-bromo-isopropoxybenzene (25.3 g, 118 mmol) as a colorless liquid.

[0411] Step 2

[0412] A mixture of magnesium (0.534 g, 22.0 mmol) and tetrahydrofuran(20 mL) under nitrogen was brought to reflux. To the solution was slowlyadded 4-bromo-isopropoxybenzene (3.10 g, 14.4 mmol) and to ensureinitiation of the reaction 1,2-dibromoethane (0.74 g, 3.93 mmol). Aftercompletion of the Grignard reaction, the solution was cooled to roomtemerature and 0.5M zinc chloride in tetrahydrofuran (14.5 mL, 7.3 mmol)was added. The solution was warmed to reflux to 30 minutes then cooledto room temperature.

[0413] Step 3

[0414] A mixture of 4-nitrobenzoyl chloride (1.47 g, 7.92 mmol),tetrakis(triphenylphosphine)palladium (0.46 g, 0.40 mmol), andtetrahyrofuran (10 mL) under nitrogen was cooled in an ice water bath.To the solution was added a portion of the diarylzinc solution (3.5mmol). The solution was stirred for 1 hour in the ice water bath, thenovernight at room temperature. The solution was diluted with water (15mL) and concentrated. The concentrate was extracted withdichloromethane. The extract was dried (MgSO₄), filtered andconcentrated. The residue was purified using silica gel chromatographyto give 4-isopropoxybenzoyl-4-nitrobenzene (1.0 g, 3.5 mmol), m.p.135.6-136.9° C.

[0415] Last Step

[0416] Proceeding as described in Example 1, last step, gave2-[4-(4-isopropoxbenzyl)-phenyl]amino-imidazoline, as an identicalproduct as that obtained in Example 1.

Example 4 2-[4-(4-Isopropoxymethylbenzyl)phenyl]-amino-imidazoline

[0417] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ia in which R¹ is agroup represented by formula (A), R² and R⁴ are hydrogen, Y isisopropyl, and m is an integer 1.

[0418] Step 1

[0419] To a stirred solution of 1-bromo-4-isopropoxymethyl-benzene (300mg, 13.1 mmol) (prepared as described in Preparation 1) in drytetrahydrofuran (1.4 mL) at −78° C. under argon atmosphere was addeddropwise 1.7M tert-butyllithium in pentane (1.62 mL, 2.75 mmol). Afterthe mixture was stirred for about 20 minutes, tri-n-butyltin chloride(0.35 mL, 1.31 mmol) was added. The mixture was allowed to reach 0° to5° C. and stirred for about 1 hour. A mixture of (4-chloromethylphenyl)carbamic acid 2-trimethylsilanyl-ethyl ester (374 mg, 13.1 mmol)(prepared as described in Preparation 2), hexamethylphosphoramide (4.4mL), tetrakis(triphenylphosphine)palladium(0) (29.3 mg, 0.025 mmol) wasadded at 0° to 5° C., and then heated to about 65° C. for 20 hours. Thesolution was partitioned between water (15 mL) and diethyl ether (15mL). The aqueous phase was extracted with diethyl ether, and thecombined organic layers were washed with water and brine, dried(Na₂SO₄), and evaporated in vacuo. The residue was dissolved inacetonitrile, washed with hexane (2×20 mL), dried (Na₂SO₄), concentratedin vacuo, and purified by flash chromatography to give pure4-(4-isopropoxymethylbenzyl)phenyl carbamic acid2-trimethylsilanyl-ethyl ester (204 mg, 26%) as clear oil.

[0420] Step 2

[0421] To a solution of 4-(4-isopropoxymethylbenzyl)phenyl carbamic acid2-trimethylsilanyl-ethyl ester (734 mg, 1.84 mmol) in dry dimethylsulfoxide at 20° C. under argon atmosphere was addedtetra-n-butylammonium fluoride in tetrahydrofuran (5.52 mL, 5.52 mmol).After the mixture was stirred for 1 hour, the solution was partitionedbetween water (50 mL) and diethyl ether (50 mL). The aqueous phase wasextracted with diethyl ether (2×20 mL), and the combined organic layerswere washed with water and brine, dried (Mg₂SO₄), and evaporated invacuo. The crude product was purified by flash chromatography to givepure 4-(4-isopropoxymethyl-benzyl)-phenylamine (405 mg, 86%) as a clearoil.

[0422] Last Step

[0423] To a solution of 4-(4-isopropoxymethylbenzyl)-phenylamine (400mg, 1.57 mmol) in isopropanol (4.8 mL) at 20° C. under argon atmospherewas added 2-chloro-2-imidazoline sulfate (382 mg, 1.88 mmol). Themixture was heated to 80° C. and stirred for 3 hours. The solvent wasevaporated in vacuo, and water and 10% sodium hydroxide was added to pH11-12. The basic aqueous phase was extracted with dichloromethane (3×20mL), and the combined organic layers were washed with water, dried(Na₂SO₄), and evaporated in vacuo. The crude product was purified byflash chromatography, washed with 0.07M potassium carbonate, andconcentrated to give pure2-[4-(4-isopropoxymethyl-benzyl)-phenyl]-imidazoline (463 mg, 91%) as aclear oil.

[0424] Oxalic acid (129 mg, 1.43 mmol) was added to2-[4-(4-isopropoxymethyl-benzyl)-phenyl]-imidazoline and recrystallizedfrom acetone to give2-[4-(4-isopropoxymethyl-benzyl)-phenyl]-imidazoline oxalate (507 mg) asa white crystalline solid, m.p. 156.3-156.7° C.; Analysis forC₂₀H₂₅N₃O.C₂H₂O₄: Calc.: C, 63.91; H, 6.58; N, 10.16; Found: C, 63.98;H, 6.53; N, 10.24.

[0425] Proceeding as in described in Example 4, step 1, but replacing1-bromo-4-isopropoxymethyl-benzene with1-bromo-4-sec-butoxymethyl-benzene, and then correspondingly as insubsequent steps, gave2-[4-(4-sec-butoxymethylbenzyl)-phenyl]-imidazoline oxalate, m.p.145.0-145.3° C.; Analysis for C₂₁H₂₇N₃O.C₂H₂O₄: Calc.: C, 64.62; H,6.84; N, 9.83; Found: C, 64.81; H, 6.82; N, 9.98.

Example 5 2-[4-(4-Morpholinobenzyl)phenyl]amino-imidazoline

[0426] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ib in which R¹ is agroup represented by formula (A), R² and R⁴ are hydrogen, and R³ ismorpholino.

[0427] Step 1

[0428] Aluminum chloride (26.0 g, 195 mmol) was added in portions to asolution of 4-nitrobenzoyl chloride (27.8 g, 150 mL) and 4-fluorobenzene(15.8 g, 165 mmol) in carbon disulfide (100 mL). After 1 hour, theresulting yellow mixture was carefully treated with concentratedhydrochloric acid (60 mL) and stirred for 30 minutes. The mixture wasthen diluted with water and extracted with ethyl acetate. The organiclayer was washed with dilute sodium hydroxide solution, water and brine,dried (MgSO₄), and the solvent removed in vacuo. Crystallization fromethyl ether/hexanes gave 4-(4-fluorobenzoyl)-nitrobenzene (10.6 g, 82%)as a white solid, m.p. 87-88° C.; Analysis for C₁₃H₈NO₃F: Calc.: C,63.69; H, 3.26; N, 5.71: Found: C, 63.89; H, 3.28; N, 5.78.

[0429] Step 2

[0430] A mixture containing 4-(4-fluorobenzoyl)-nitrobenzene (1.96 g, 8mmol), morpholine (0.84 g, 9.6 mmol), and potassium carbonate (1.33 g,9.6 mmol) in dimethyl sulfoxide (15 mL) was heated to 100-110° C. for 12hours. The reaction mixture was cooled to room temperature and dilutedwith cold water, and filtered. The crude product was washed severaltimes with water and dried to give 4-(4-morpholinobenzoyl)-nitrobenzene(2.28 g, 91%), m.p. 173-175° C., and was used in the next step withoutfurther purification.

[0431] Step 3

[0432] 4-(4-Morpholinobenzoyl)-nitrobenzene (1.0 g) was hydrogenated at50 psi using 10% palladium on carbon in ethanol and mineral acid asdescribed previously in Example 1, Step 5. The product thus obtained,4-(4-morpholinobenzyl)-phenylamine (0.66 g, 77%) was used in the nextstep without further purification.

[0433] Last Step

[0434] Proceeding as described in Example 1, last step, but replacing4-(4-isopropoxybenzyl)-phenylamine with4-(4-morpholinobenzyl)-phenylamine (0.63 g), gave2-[4-(4-morpholinobenzyl)phenyl]amino-imidazoline (0.51 g, 63%), m.p.177-179° C.; Analysis for C₂₀H₂₄N₄O: Calc.: C, 71.44; H, 7.14; N, 16.66;Found: C, 71.62; H, 7.24; N, 16.41.

[0435] Proceeding as in Example 5, step 1, and then correspondingly asin Example 5, step 3 and last step, gave2-[4-(4-fluorobenzyl)phenyl]amino-imidazoline, m.p. 110-112° C.

[0436] Proceeding as in Example 5, step 2, but replacing morpholine withN,N-(2-hydroxyethyl)amine, and then correspondingly as in Example 5,subsequent steps, gave2-{4-[4-(N,N-(2-hydroxyethyl)amino)-benzyl]phenyl}amino-imidazoline,m.p. 150-152° C.

[0437] Proceeding as in Example 5, step 1, but replacing 4-fluorobenzenewith 2,4-difluorobenzene, and then correspondingly as in Example 5, step3 and last step, gave 2-[4-(2,4-difluorobenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 150-152° C. Proceeding as in Example 5, step 1, butreplacing 4-fluorobenzene with alkylated benzenes, and thencorrespondingly as in Example 5, subsequent steps, the followingcompounds of Formula I were prepared:

[0438] 2-[4-(4-ethylbenzyl)phenyl]amino-imidazoline hydrochloride, m.p.72-74° C.;

[0439] 2-[4-(4-isopropylbenzyl)phenyl]amino-imidazoline fumarate,Analysis for C₁₉H₂₃N₃0.75C₄H₄O₂: Calc.: C, 62.60; H, 6.28; N, 9.78;Found: C, 62.61, H, 6.44; N, 10.00;

[0440] 2-14-(4-isobutylbenzyl)phenyl]amino-imidazoline fumarate, m.p.182-184° C.;

[0441] 2-{4-(4-(3-methylbutyl)benzyl]phenyl)amino-imidazolinehydrochloride, Analysis for C₂₁H₂₈N₃Cl: Calc.: C, 69.94; H, 7.91; N,7.76; Found: C, 69.84, H, 11.65, N, 11.75;

[0442] 2-[4-(4-propylbenzyl)phenyl]amino-imidazoline hydrochloride,Analysis for C₁₉H₂₄N₃O: Calc.: C, 68.07; H, 7.39; N, 12.53; Found: C,68.05, H, 7.21, N, 12.70;

[0443] 2-[4-(4-cyclopentyl)benzyl]phenyl)amino-imidazoline fumarate,Analysis for C₂₅H₂₉N₃O₄: Calc.: C, 62.20; H, 6.19; N, 8.43; Found: C,62.42, H, 6.23, N, 8.63; and

[0444] 2-[4-(4-cyclohexyl)benzyl)phenyl]amino-imidazoline fumarate,Analysis for C₂₂H₂₈N₃Cl: Calc.: C, 68.43; H, 7.78; N, 10.88; Found: C,68.36, H, 7.45, N, i 1.23.

Example 62-{4-[4-(4-Methoxyphenyl)sulfonylaminomethylbenzyl]-phenyl}amino-imidazoline

[0445] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ic in which R¹ is agroup represented by formula (A), R², R⁴ and R⁷ are hydrogen, R⁹ is4-methoxyphenyl, and m is an integer 1.

[0446] Step 1

[0447] Aluminum chloride (9.3 g) was added in a single portion to amixture of 4-nitrobenzoyl chloride (10 g) and toluene (6.3 mL) dissolvedin carbon disulfide (35 mL). The mixture was warmed from roomtemperature to reflux and heated for 3 hours. Concentrated hydrochloricacid (19 mL) was slowly added, and the mixture stirred for an additional30 minutes, poured into water, and extracted with dichloromethane (3×).The extract was washed with dilute ammonium hydroxide and water, dried(Na₂SO₄), and evaporated. Recrystallization from ethyl acetate gave4-(4-methylbenzoyl)-nitrobenzene (10.6 g, 82%) as a pale yellow solid,M.p. 122.4-123.1° C.

[0448] Step 2

[0449] Benzoyl peroxide (0.012 g) was added to a mixture of4-(4-methylbenzoyl)-nitrobenzene (1.20 g) and N-bromosuccinimide (0.89g) suspended in carbon tetrachloride (63 mL). The reaction mixture wasrefluxed under argon for 4 hours while illuminated with an incandescentlamp. The mixture was filtered, and the yellow solution containing thecrude product was evaporated, chromatographed on silica gel, elutingwith hexane/ethyl acetate, to give 4-(4-bromomethylbenzoyl)-nitrobenzene(1.79 g, 81%) as a white solid, m.p. 112.7-113.1° C.

[0450] Step 3

[0451] 4-(4-bromomethylbenzoyl)-nitrobenzene (500 mg) was dissolved indichloromethane (5 mL) and stirred under argon. A solution oftrifluoromethanesulfonic acid (0.27 mL) in dichloromethane (2 mL) wasadded dropwise, followed by a solution of triethylsilane (0.37 mL) indichloromethane (2 mL). After 5 minutes, a second portion oftrifluoromethanesulfonic acid and triethylsilane (same proportions) wasadded. The reaction mixture was stirred at room temperature for 3 hours,poured into excess aqueous sodium bicarbonate, and extracted withdichloromethane (3×). The solution containing the crude product wasevaporated, chromatographed on silica gel, eluting the product withhexane/ethyl acetate, and evaporated to dryness, to give4-(4-bromomethylbenzyl)-nitrobenzene (270 mg, 56%).

[0452] Step 4

[0453] Sodium azide (210 mg, 1.15 eq) was added to a solution of4-(4-bromomethylbenzyl)-nitrobenzene (901 mg) in N,N-dimethylformamide(10 mL). The reaction mixture was stirred at room temperature for 2hours, poured into water, and extracted with diethyl ether (3×). Theorganic phase was washed with water (3×), dried (MgSO₄), and evaporatedto dryness. Chromatography on silica gel, eluting with hexane/ethylacetate, gave 4-(4-azidomethylbenzyl)-nitrobenzene (492 mg, 62%) as ayellow oil.

[0454] Step 5

[0455] A solution of 4-(4-azidomethylbenzyl)-nitrobenzene (5.835 g) intetrahydrofuran (175 mL) was treated with water (0.43 mL) andtriphenylphosphine (6.45 g, 1.1 eg). The mixture was stirred at roomtemperature for 18 hours, and the solvent was evaporated. The residuewas suspended in water, and suspension made acidic by the dropwiseaddition of hydrochloric acid to about pH 1, then extracted with diethylether (3×). The aqueous phase was made alkaline with 50% aqueous sodiumhydroxide, extracted with dichloromethane (3×) to afford a crude brownoil (5.66 g). Chromatography on silica gel, eluting withdichloromethane/methanol/ammonium hydroxide, gave4-(4-aminomethylbenzyl)-nitrobenzene (3.91 g, 79%) as a yellow solid.

[0456] Step 6

[0457] 4-(4-Aminomethylbenzyl)-nitrobenzene (500 mg) was dissolved indichloromethane (7 mL) and heated with 4-methoxybenzenesulfonyl chloride(426 mg) and triethylamine (0.3 mL). The mixture was stirred at roomtemperature for 15 hours, poured into dilute aqueous hydrochloric acid,and extracted with dichloromethane (3×). The solvent was evaporated togive 4-[4-(4-methoxyphenyl)sulfonylaminomethylbenzyl]-nitrobenzene as ayellow solid (851 mg, 100%), and was used in the next step withoutfurther purification.

[0458] Step 7

[0459] 4-[4-(4-Methoxyphenyl)sulfonylaminomethylbenzyl]-nitrobenzene(791 mg) was dissolved in ethyl acetate (15 mL) and hydrogenated over 5%palladium on carbon at room temperature. The reaction was allowed toproceed for 6 hours, filtered, and evaporated to dryness. The crudeproduct thus obtained was chromatographed on a short silica column,eluting with hexane/ethyl acetate (1:1), to give4-[4-(4-methoxyphenyl)sulfonylaminomethylbenzyl]-phenylamine (645 mg,87%) as a yellow solid.

[0460] Last Step

[0461] Proceeding as described in Example 1, last Step, but replacing4-(4-isopropoxybenzyl)-phenylamine with4-[4-(4-methoxyphenyl)-sulfonylaminomethylbenzyl]-phenylamine (645 mg),concentrating solvents, and chromatography on silica gel, eluting withdichloromethane/methanol/ammonium hydroxide (60:10:1), and recrystallingfrom acetone with oxalic acid (134 mg, 1 eq), gave2-(4-[4-(4-methoxyphenyl)sulfonylaminomethylbenzyl]-phenyl)amino-imidazolineoxalate (685 mg, 75%) as a white solid, m.p. 167.0-167.5° C.; Analysisfor C₂₆H₂₈N₄O₇S: Calc.: C, 57.89; H, 5.11; N, 10.47; Found: C, 57.77; H,5.22; N, 10.36.

[0462] Proceeding as in Example 6, step 6, but replacing4-methoxybenzenesulfonyl chloride with other sulfonyl chlorides, andthen correspondingly in Example 6, subsequent steps, the followingcompounds of Formula I were prepared:

[0463]2-[4-(4-benzenesulfonylaminomethylbenzyl)-phenyl]amino-imidazolinehydrochloride, m.p. 228.2-229.2° C.;

[0464]2-{4-[4-(4-fluorophenyl)sulfonylaminomethylbenzyl]-phenyl}amino-imidazolineoxalate, m.p. 170.0-171.2° C;

[0465]2-{4-[4-(2-fluorophenyl)sulfonylaminomethylbenzyl]-phenyl)amino-imidazolineoxalate, m.p. 94.4-95.6° C.;

[0466]2-[4-(4-isopropylsulfonylaminomethylbenzyl)phenyl]amino-imidazolineoxalate, m.p. 128.5-129.5° C.; and

[0467] 2-[4-(4-propylsulfonylaminomethylbenzyl)phenyl]amino-imidazolineoxalate, m.p. 122.8-123.5° C.

Example 7 2-[4-(4-Ethanesulfonylaminobenzyl)phenyl]amino-imidazoline

[0468] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ic′ in which R¹ isa group represented by formula (A), R² and R⁴ are hydrogen, R⁹ is ethyl,and m is an integer 0.

[0469] Step 1

[0470] Ethanesulfonyl chloride (1.1 mL, 10 mmol) was added in oneportion to a solution of 4,4′-methylenedianiline (1.98 g, 10 mmol) indichloromethane (25 mL). The reaction mixture was stirred for 1 hour andevaporated to give a solid, which was dissolved in dichloromethane (50mL) and poured into diethyl ether/2% aqueous potassium carbonate (1:1).After extraction, the aqueous layer was drawn off and discarded.

[0471] The organic layer was extracted with 1% aqueous potassiumhydroxide (2×100 mL) and the aqueous layer was treated with excesscarbon dioxide and extracted with dichloromethane (3×25 mL). Thedichloromethane layer was diluted with diethyl ether (125 mL) andextracted with 1% aqueous hydrochloric acid (2×100 mL). The layers wereagain separated and the aqueous phase was extracted with diethyl ether(50 ml), and the organic phases were discarded. The aqueous phase, whichcontained the product, was neutralized with solid potassium carbonate,extracted with dichloromethane (4×20 ml), and evaporated to dryness.Recrystallization from acetone/hexanes gave4-[4-(ethanesulfonyl)aminobenzyl]-phenylamine (940 mg, 32%) as whiteneedles, m.p. 108-109° C.

[0472] Last Step

[0473] Proceeding as described in Example 1, last step, but replacing4-(4-isopropoxybenzyl)-phenylamine with4-[4-(ethanesulfonyl)-aminobenzyl]-phenylamine (290 mg, 1 mmol), andcrystallization from ethyl acetate, gave2-[4-(4-ethanesulfonylaminobenzyl)-phenyl]amino-imidazoline (319 mg,89%).

[0474] The hydrochloride salt was obtained by suspending the free basein methanol (10 mL) and adding ethanolic hydrochloric acid until acidic.The solvents were stripped, and product was refluxed with stirring inethyl acetate (5 mL). The product,2-[4-(4-ethanesulfonylamino-benzyl)-phenyl]amino-imidazolinehydrochloride was filtered and dried, m.p. 178-178.5° C.; Analysis forC₁₈H₂₃ClN₄O₂S: Calc.: C, 54.74; H, 5.87; N, 14.19; Found: C, 54.65; H,5.79; N, 14.21.

[0475] Proceeding as in Example 7, step 1, but replacing ethanesulfonylchloride with other sulfonyl chlorides, and then correspondingly as inExample 7, subsequent steps, the following compounds of Formula I wereprepared:

[0476] 2-{4-[4-benzenesulfonylaminobenzyl]phenyl)amino-imidazolinehydrochloride, Analysis for C₂₂H₂₃ClN₄O₂S: Calc.: C, 57.89; H, 5.41; N,12.27; Found: C, 57.66; H, 5.17; N, 11.95;

[0477]2-{4-[4-(4-methylphenyl)sulfonylaminobenzyl]phenyl}amino-imidazolinehydrochloride, Analysis for C₂₃H₂₅ClN₄O₂S: Calc.: C, 59.40; H, 5.61; N,12.07; Found: C, 59.59; H, 5.64; N, 11.66;

[0478] 2-[4-(4-isopropylsulfonylaminobenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 206.6-207° C.;

[0479] 2-[4-(4-methanesulfonylaminobenzyl)phenyl]amino-imidazolinehe?mioxalate, m.p. 254.2-254.5° C.;

[0480] 2-[4-(4-benzylsulfonylaminobenzyl)phenyl]amino-imidazolinehydrochloride, Analysis for C₂₃H₂₅ClN₄O₂S: Calc.: C, 60.45; H, 5.51; N,12.26; Found: C, 60.33; H, 5.67; N, 12.39;

[0481]2-{4-[4-(2,2,2-trifluoroethyl)sulfonylaminobenzyl]phenyl}amino-imidazolinehydrochloride, Analysis for C₁₈H₂₀ClF₃N₄O₂S: Calc.: C, 48.16; H, 4.49;N, 12.48; Found: C, 47.89; H, 4.47; N, 12.33;

[0482] 2-[4-(4-propylsulfonylaminobenzyl)phenyl]amino-imidazolinehydrochloride, Analysis for C₁₉H₂₅ClN₄O₂S: Calc.: C, 55.56; H, 6.18; N,13.64; Found: C, 55.34; H, 6.17; N, 13.44;

[0483] 2-[4-(4-butylsulfonylaminobenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 157-160° C.;

[0484]2-{4-[4-(4-methoxyphenyl)sulfonylaminobenzyl]phenyl}amino-imidazolinehydrochloride, Analysis for C₂₃H₂₅ClN₄O₃S: Calc.: C, 57.96; H, 5.35; N,11.76; Found: C, 57.81; H, 5.35; N, 11.58;

[0485] 2-{4-[4-(thien-2-ylsulfonyl)aminobenzyl]phenyl}amino-imidazolinehydrochloride, m.p. 109.5-110° C.; and

[0486] 2-[4-(4-dimethylaminosulfonylaminobenzyl)phenyl]amino-imidazolinehydrochloride, m.p. 198.5-201° C.

[0487] Proceeding as in Example 7, step 1, but replacing ethanesulfonylchloride with carbonyl chlorides, and then correspondingly as in Example7, subsequent steps, the following compounds of Formula I were preparedfrom the corresponding compound of formula Id:

[0488]2-{4-[4-(tetrahydropyran-4-ylcarbonyl)aminobenzyl]phenyl}amino-imidazoline,m.p. 225-227° C.; and

[0489] 2-{4-[4-(isopropylcarbonyl)aminobenzyl]phenyl]amino-imidazolinehydrochloride, m.p. gum.

Example 82-(4-[4-(Ethanesulfonyl)methylaminobenzyl]phenyl)amino-imidazoline

[0490] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ic in which R¹ is agroup represented by formula (A), R² and R⁴ are hydrogen, R⁷ is methyl,R⁹ is ethyl, and m is an integer 0.

[0491] Solid potassium tert-butoxide (113 mg, 1 mmol) was added to asolution of 4-(4-ethanesulfonylaminobenzyl)-phenylamine (290 mg)(prepared as described in Example 7) in dimethyl sulfoxide (2 mL). Themixture was stirred and methyl iodide (0.1 mL, 1.5 mmol) was added.After 1 hour, the reaction mixture was poured into water and extractedwith diethyl ether (2×). The organic phase was dried on potassiumcarbonate, evaporated and chromatographed on silica gel, eluting withdichloromethane/acetone, to give4-[4-(ethanesulfonyl)methylaminobenzyl]-phenylamine (200 mg, 66%) as ayellow solid.

[0492] Proceeding as described in Example 1, last step, but replacing4-(4-isopropoxybenzyl)-phenylamine with4-[4-(ethanesulfonyl)methylaminobenzyl]-phenylamine (300 mg, 0.99 mmol),refluxing the reaction mixture in isopropanol for 16 hours, andcrystallization from ethyl acetate/hexanes gave2-(4-[4-(ethanesulfonyl)methylaminobenzyl]-phenyl}amino-imidazoline (318mg, 89%). The free amine was then converted to the hydrochloride salt.m.p. 178-178.5° C.; Analysis for C₁₉H₂₃ClN₄O₂S: Calc.: C, 53.68; H,6.35; N, 13.18; Found: C, 53.72; H, 6.01; N, 13.09.

[0493] Proceeding as in Example 8, but replacing methyl iodide withother alkyl iodides, and then correspondingly as in Example 8, thefollowing compounds of Formula I were prepared:

[0494]2-(4-[4-(methanesulfonyl)benzylaminobenzyl]phenyl)amino-imidazolinehydrochloride, Analysis for C₂₄H₂₇ClN₄O₂S: Calc.: C, 58.08; H, 5.95; N,10.41; Found: C, 57.97; H, 5.94; N, 10.58;

[0495]2-{4-[4-(isopropylsulfonyl)methylaminobenzyl]phenyl}amino-imidazolin ehydrochloride, Analysis for C₂₀H₂₇ClN₄O₂S: Calc.: C, 55:15; H, 6.57; N,12.86; Found: C, 55.11; H, 6.39; N, 12.76;

[0496]2-{4-[4-(propylsulfonyl)methylaminobenzyl]phenyl}amino-imidazolinehydrochloride, Analysis for C₂₀H₂₇ClN₄O₂S: Calc.: C, 56.31; H, 6.47; N,13.13; Found: C, 56.10; H, 6.34; N, 13.04;

[0497] 2-{4-[4-(ethanesulfonyl)ethylaminobenzyl]phenyl}amino-imidazolinehydrochloride, Analysis for C₂₁H₂₉ClN₄O₂S: Calc.: C, 56.55; H, 6.78; N,12.56; Found: C, 56.51, H, 6.61; N, 12.51; and

[0498]2-{4-[4-(ethanesulfonyl)propylaminobenzyl]phenyl}amino-imidazolinehydrochloride, Analysis for C₂₂H₃₁ClN₄O₂S: Calc.: C, 54.47; H, 6.62; N,12.70; Found: C, 54.40, H, 6.44; N, 12.59.

Example 92-{4-[4-(1,1-Dioxo-isothiazolidin-1-yl)benzyl]-phenyl}amino-imidazoline

[0499] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ic in which R¹ is agroup represented by formula (A), R² and R⁴ are hydrogen, R³ is1,1-dioxo-isothiazolidin-1-yl.

[0500] 4-[4-(3-Chloropropyl)sulfonylaminobenzyl]-phenylamine (1.40 g,3.9 mmol) (prepared as described in Example 7) was stirred in a solutionof tetrahydrofuran (25 mL) containing 60% sodium hydride (180 mg, 4.5mmol). The mixture was refluxed for 16 hours, poured into water, andextracted with dichloromethane (3×). Evaporation and recrystallizationgave pure 4-[4-(1,1-dioxo-isothiazolidine)-benzyl]-phenylamine (1.09 g,86%) as an off-white solid, m.p. 134.5-135.5° C.

[0501] Proceeding as described in Example 1, last step, but replacing4-(4-isopropoxybenzyl)-phenylamine with4-[4-(1,1-dioxo-isothiazolidin-1-yl)-benzyl]-phenylamine gave2-{4-[4-(1,1-dioxo-isothiazolidin-1-yl)benzyl]-phenyl}amino-imidazoline;m.p. 197.2-198.5° C.; Analysis for C₂₁H₂₄N₄O₆S: Calc.: C, 54.74; H,5.25; N, 12.17; Found: C, 54.63; H, 5.28; N, 12.11.

Example 10 2-{4-[4-(3-Phenylureido)benzyl]phenyl}amino-imidazoline

[0502] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ie in which R¹ is agroup represented by formula (A), R², R⁴, R⁷ and R⁸ are hydrogen; R⁹ isphenyl, V is 0, and m is an integer 0.

[0503] Step 1

[0504] A mixture of 4,4′-methylenedianiline (19.8 g), potassiumcarbonate (20 g) in ethyl acetate (300 mL) and water (200 mL) wasstirred in an ice bath. Benzyl chloroformate (15 mL) was slowly added tothe mixture. The resulting mixture was stirred for 1 hour, then theorganic layer was separated, and the aqueous layer extracted withadditional ethyl acetate. The combined organic extracts were washed withwater and brine, dried (Na₂SO₄), and the solvent removed in vacuo. Thecrude mixture was isolated by column chromatography on silica gel,eluting with 30% ethyl acetate/hexanes, to give4-(4-aminobenzyl)phenyl-carbamic acid benzyl ester as solid.

[0505] Step 2

[0506] 4-(4-Aminobenzyl)phenyl-carbamic acid benzyl ester (0.997, 3mmol) was added to a solution of phenylisocyanate (0.393 g, 3.3 mmol) indichloromethane (20 mL). The reaction mixture was stirred for 1 hour atroom temperature under nitrogen. The reaction mixture was quenched withwater and concentrated in vacuo. The residue was suspended in water,filtered, washed with water, and dried to give(4-[4-(3-phenylureido)benzyl]phenyl}-carbamic acid benzyl ester (1.38 g)as a white solid.

[0507] Step 3

[0508] A mixture of 4-[4-(3-phenylureido)benzyl]phenyl-carbamic acidbenzyl ester (1.3 g) and 10% palladium on carbon (0.35 g) in ethanol(150 mL) was hydrogenated at 50 psi in a Parr apparatus for 12 hours.The reaction mixture filtered through a Celite pad to remove catalyst.The filtrate on concentration gave4-[4-(3-phenylureido)benzyl]-phenylamine (0.76 g) as white solid.

[0509] Last Step

[0510] A mixture of 4-[4-(3-phenylureido)benzyl]-phenylamine (0.7 g,2.21 mmol) and 2-chloro-2-imadazoline sulfate (0.673 g, 3.32 mmol) in2-propanol (20 mL) was heated under reflux for 1 hour. The reactionmixture was concentrated, diluted with dichloromethane and basified witha 10% sodium hydroxide solution. The organic layer was separated, andthe aqueous layer extracted with additional dichloromethane. Thecombined organic extracts were washed with water and brine, dried(K₂CO₃), and the solvent removed in vacuo. The residue waschromatographed on aluminum oxide (neutral, activity 1, 15%methanol/dichloromethane) to give2-(4-[4-(3-phenylureido)benzyl]phenyl}amino-imidazoline as a whitesolid, m.p. 167-170° C.; Analysis for C₂₃H₂₃N₅O: Calc.: C, 71.70; H,5.97; N, 18.18; Found: C, 71.34; H, 5.98; N, 17.91.

[0511] Proceeding as described in Example 6, step 6, but replacing4-methoxybenzene-sulfonyl chloride with phenylisocyanate, and thencorrespondingly as in Example 6, gave2-{4-[4-(3-phenylureido)methylbenzyl]phenyl}-amino-imidazoline fumarate,m.p. 207-208.5° C.

Example 11 2-[4-(4-Dimethylaminosulfonylbenzyl)-phenyl]amino-imidazoline

[0512] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula If in which R¹ is agroup represented by formula (A), R² and R⁴, R⁸ and R⁹ are each methyl,and m is an integer 0.

[0513] Step 1

[0514] A solution of 4-benzyl-nitrobenzene (4.26 g, 70 mmol) dissolvedin dichloromethane (25 mL) was added dropwise to a solution ofchlorosulfonic acid (6 mL) in dichloromethane (25 mL) at −30° C. Themixture was stirred for 10 minutes at 0° C., then poured onto ice andshaken. The organic phase was separated and solvents were evaporated.The residue was recrystallized from dichloromethane/hexanes to yield4-(4-chlorosulfonylbenzyl)-nitrobenzene (5.52 g, 78%) as dichloromethanehemisolvate crystals.

[0515] Step 2

[0516] A solution of dimethylamine in tetrahydrofuran (2M, excess) wasadded 4-(4-chlorosulfonylbenzyl)-nitrobenzene dichloromethanehemisolvate (354 mg, 1 mmol) dissolved in tetrahydrofuran (5 mL). Themixture was stirred for 1 hour and extracted with a solution of diethylether and dilute potassium carbonate. The organic layer was separatedand solvents evaporated. The residue was recrystallized fromacetone/hexanes to give 4-(4-dimethylaminosulfonylbenzyl)-nitrobenzene(311 mg, 98%).

[0517] Step 3

[0518] 4-(4-Dimethylaminosulfonylbenzyl)-nitrobenzene (311 mg) wasdissolved in ethyl acetate and hydrogenated at 40 psi using a 10%palladium on carbon catalyst for 2 hours. The mixture was filtered, andsolvents evaporated to give4-(4-dimethylaminosulfonylbenzyl)-phenylamine as a white solid (288 mg,99%).

[0519] Last Step

[0520] A mixture of 4-(4-dimethylaminosulfonylbenzyl)-phenylamine (288mg) and 2-chloro-imidazoline sulfate (110 mg) in 2-propanol was heatedunder reflux for 16 hours. A dilute solution of potassium carbonate waspoured into the mixture and extracted with dichloromethane (4×15 mL).Solvents were evaported to give2-[4-(4-dimethylaminosulfonylbenzyl)-phenyl]amino-imidazoline as a solid(320 mg).

[0521] The product was dissolved in ethyl acetate and treated withexcess methanolic hydrogen chloride to give a crude product. Solventswere evaporated and the residue was recrystallizated from2-propanol/ethyl acetate to give2-[4-(4-dimethylaminosulfonylbenzyl)-phenyl]amino-imidazolinehydrochloride as a white solid (292 mg, 76%), m.p. 194.1-195.3° C.;Analysis for C₁₈H₂₃ClN₄O₂S: Calc.: C, 54.99; H, 5.87; N, 14.19; Found:C, 54.74; H, 5.87; N, 13.96.

[0522] Proceeding as described in Example 11, step 2, but replacingdimethylamine with other amines, and then correspondingly as in Example11, subsequent steps, other compounds of Formula I were prepared:

[0523] 2-[4-(4-benzylaminosulfonylbenzyl)-phenyl]amino-imidazolinehydrochloride, m.p. glass; Analysis for C₂₃H₂₃ClN₄O₂S.0.7H₂O: Calc.: C,59.04; H, 5.45; N, 11.97; Found: C, 59.05; H, 5.42; N, 11.90;

[0524] 2-[4-(4-isobutylaminosulfonylbenzyl)-phenyl]amino-imidazolinehydrochloride, m.p. glass; Analysis for C₂₀H₂₇ClN₄O₂S.0.7H₂O: Calc.: C,55.36; H, 6.34; N, 12.91; Found: C, 55.38; H, 6.21; N, 12.66;

[0525] 2-[4-(4-pyrrolidin-1-ylsulfonylbenzyl)-phenyl]amino-imidazolinehydrochloride, m.p. 190.0-191.2° C.; Analysis for C₂₀H₂₅ClN₄O₂S: Calc.:C, 57.06; H, 5.99; N, 13.31; Found: C, 56.97; H, 5.93; N, 13.15;

[0526] 2-[4-(4-isopropylaminosulfonylbenzyl)-phenyl]amino-imidazolineoxalate, m.p. 138.0-140.5° C.; Analysis for C₂₁H₂₆N₄O₆S: Calc.: C,54.53; H, 5.67; N, 12.11; Found: C, 54.39; H, 5.58; N, 12.02;

[0527] 2-[4-(4-diisopropylaminosulfonylbenzyl)-phenyl]amino-imidazolinehydrochloride, m.p. glass; Analysis for C₂₂H₃₁ClN₄O₂S.0.5H₂O: Calc.: C,57.57; H, 6.81; N, 12.20; Found: C, 57.67; H, 6.85; N, 11.81;

[0528] 2-[4-(4-t-butylaminosulfonylbenzyl)-phenyl]amino-imidazolineoxalate, m.p. glass, Analysis for C₂₂H₂₈N₄O₆S.H₂O: Calc.: C, 53.43; H,6.11; N, 11.33; Found: C, 53.67; H, 6.30; N, 11.03; and

[0529] 2-[4-(4-butylaminosulfonylbenzyl)-phenyl]amino-imidazolineoxalate, m.p. 153.6-154.4° C., Analysis for C₂₂H₂₈N₄O₆S: Calc.: C,55.45; H, 5.92; N, 11.76; Found: C, 55.23; H, 5.80; N, 11.67.

Example 122-[4-(4-Benzylaminosulfonylmethylbenzyl)-phenyl]amino-imidazoline

[0530] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula If in which R¹ is agroup represented by formula (A), R², R⁴ and R⁸ are hydrogen, R⁹ isbenzyl, and m is an integer 1.

[0531] Alternative Step 1a

[0532] A solution of sodium sulfite (0.73 g, 7 mmol) dissolved in water(10 mL) was added to a solution of 4-(4-bromomethylbenzyl)-nitrobenzene(1.41 g, 5.6 mmol) in acetonitrile (10 mL). The mixture was stirred andheated under reflux for 2 hours. Solvents were evaporated and dried togive the 4-(4-nitrobenzyl)-phenylmethanesulfonic acid sodium salt as awhite powder (2.29 g).

[0533] Alternative Step 1b

[0534] 4-(4-Nitrobenzyl)-phenylmethanesulfonic acid sodium salt (2.29 g)was combined with phosphorus pentachloride (1.45 g). The mixture washeated to 90° C. for 5 minutes, poured into water, and extracted withdichloromethane (3×20 mL). Solvents were evaporated to give4-(4-chlorosulfonylmethylbenzyl)-nitrobenzene as an impure yellow solid(0.63 g). This product was used directly in the next step.

[0535] Step 2

[0536] Benzylamine (0.3 mL) was added to a solution of4-(4-chlorosulfonylmethyl-benzyl)-nitrobenzene (100 mg) intetrahydrofuran (4 mL). The mixture was stirred for 2 hours, poured intodilute aqueous potassium carbonate, and extracted with dichloromethane(3×15 mL). Solvents were evaporated and the residue was chromatographedon silica gel, eluting with 2% acetone in dichloromethane, to give4-(4-benzylaminosulfonylmethylbenzyl)-nitrobenzene (44 mg) as a solid.

[0537] Step 3

[0538] A solution of 4-(4-benzylaminosulfonylmethylbenzyl)-nitrobenzene(44 mg) was dissolved in ethyl acetate and hydrogenated at 40 psi with10% palladium on carbon catalyst for 2 hours. The mixture was filtered,and the solvent was evaported to give4-(4-benzylaminosulfonylmethylbenzyl)-phenylamine (39 mg) as anoff-white solid.

[0539] Last Step

[0540] A mixture of 4-(4-benzylaminosulfonylmethylbenzyl)-phenylamine(39 mg) and 2-chloro-imidazoline base (1 eq) in 2-propanol was heatedunder reflux for 16 hours. A dilute solution of potassium carbonate waspoured into the mixture and extracted with dichloromethane (4×15 mL).Solvents were evaported to give,2-[4-(4-benzylaminosulfonylmethylbenzyl)-phenyl]amino-imidazoline as asolid (41.7 mg), m.p. 115-118° C.; Analysis for C₂₄H₂₅ClN₄O₂S.H₂O:Calc.: C, 58.94; H, 5.98; N, 11.46; Found: C, 59.01; H, 5.91; N, 11.30.

[0541] Proceeding as described in Example 12, step 2, but replacingbenzylamine with other amines, and then correspondingly as in Example12, subsequent steps, other compounds of Formula I were prepared:

[0542]2-[4-(4-isobutylaminosulfonylmethylbenzyl)-phenyl]amino-imidazolinehydrochloride as a solid (51.5 mg), m.p. 113.2-114.6° C.; Analysis forC₂₁H₂₉ClN₄O₂S.0.5H₂O: Calc.: C, 56.55; H, 6.78; N, 12.56; Found: C,56.68; H, 6.67; N, 12.40;

[0543]2-[4-(4-dimethylaminosulfonylmethylbenzyl)-phenyl]amino-imidazolineoxalate (73 mg, 58%), m.p. 154.4-154.8° C.; Analysis for C₂₃H₂₈N₄O₆S:Calc.: C, 56.54; H, 5.78; N, 11.42; Found: C, 56.56; H, 5.67; N, 11.46;and

[0544]2-[4-(4-pyrrolidin-1-ylsulfonylmethylbenzyl)-phenyl]amino-imidazolineoxalate (105 mg, 63%), m.p. 160-161° C.; Analysis for C₂₁H₂₆N₄O₆S:Calc.: C, 54.53; H, 5.67; N, 12.11; Found: C, 54.48; H, 5.58; N, 12.13.

Example 132-[4-(4-Pyrrolidin-1-ylaminocarbonylbenzyl)-phenyl]amino-imidazoline

[0545] The following is an alternative the preparation of a compound ofFormula I from the corresponding compound of formula Ig in which R¹ is agroup represented by formula (A), R² and R⁴ are hydrogen, R⁸ and R⁹taken together with the nitrogen to which they are attached formpyrrolidine, and m is an integer 0.

[0546] Step 1

[0547] 10% Palladium on carbon (0.5 g) was added to a solution of4-benzoyl-benzoic acid (11.31 g, 50 mmol) in ethanol (250 mL) and 70%perchloric acid (10 mL). The suspension was hydrogenated under 40 psi atroom temperature for 8 hours. The catalyst was removed by filtration andthe filtrate made neutral with aqueous sodium bicarbonate. Solvents wereevaporated, and the residue was partitioned into ethyl acetate anddilute aqueous potassium hydroxide. The aqueous phase was acidified withhydrochloric acid. The precipitated acid was filtered, washed, and driedto give 4-benzyl-benzoic acid (10.74 g, 100%).

[0548] Step 2

[0549] 4-(4-Nitrobenzyl)-benzoic acid was prepared utilizing theprocedures described in Coon et al. J. Org. Chem. 1973, 38, 4243.

[0550] 70% Nitric acid (3.16 mL) was added dropwise to a suspension oftrifluoromethanesulfonic acid (9.34 mL, 105.6 mmol) in dichloromethane(250 mL). The suspension was cooled in a dry ice-acetone bath and asolution of 4-benzyl-benzoic acid (10.19 g, 48 mmol) in dichloromethane(50 mL) was added dropwise. The mixture was stirred for about 2 hours at−78° C. and an additional 2 hours at room temperature. The reactionmixture was poured into crushed ice. The separated organic layer waswashed with dichloromethane (2×) and the combined organic layers weredried over (Na₂SO₄), and solvents were evaporated. Recrystallization ofthe crude product from methanol/ethyl acetate gave4-(4-nitrobenzyl)-benzoic acid (9.27 g, 58%) as a yellow solid.

[0551] Step 3

[0552] 4-(4-Nitrobenzyl)-benzoic acid (1.03 g, 4 mmol) was dissolved indichloromethane (40 mL). Oxalyl chloride (0.42 mL, 1.2 eq) was added tothe mixture, followed by 1 drop of N,N-dimethylformamide. The mixturewas stirred for 1 hour at room temperature and the solvents evaporatedto give 4-(4-chlorocarbonylbenzyl)-nitrobenzene (1.10 g) as a paleyellow solid.

[0553] Step 4

[0554] 4-(4-Chlorocarbonylbenzyl)-nitrobenzene was dissolved indichloromethane (40 mL) and a solution of pyrrolidine (64 mg, 1 eq) inpyridine (0.2 mL) was added. The mixture was stirred for 2 hours at roomtemperature, washed with dilute potassium hydroxide, and solventsevaporated to yield a yellow oil. The residue was chromatographed onsilica gel, eluting with dichloromethane/methanol, to give4-(4-pyrrolidin-1-ylcarbonylbenzyl)-nitrobenzene (299 mg, 99%).

[0555] Step 5

[0556] A mixture of 4-(4-pyrrolidin-1-ylcarbonylbenzyl)-nitrobenzene(202 mg, 065 mmol), 10% palladium on carbon (110 mg), and ethanol (20mL) was hydrogenated at 40 psi for 16 hours. The mixture was filteredthrough a Celite pad, and solvents evaporated to give4-[4-(1-pyrrolidinecarbonyl)benzyl]-phenylamine as a white solid (187mg, 99%).

[0557] Last Step

[0558] A mixture of 4-[4-(1-pyrrolidinecarbonyl)benzyl]-phenylamine (182mg, 0.64 mmol) and 2-chloro-2-imidazoline bisulfate (131 mg, 1 eq) in2-propanol (30 mL) was stirred at 60° C. for 60 hours. The solvents wereevaporated, and the residue suspended in dilute potassium hydroxide. Thesuspension was extracted with dichloromethane and chromatographed onsilica gel, eluting with methanol/ammonium hydroxide, to give a whitesolid (205 mg). The white solid was extracted with ethyl acetate, washedwith dilute potassium hydroxide, and treated with excess hydrochloricacid in diethyl ether to give2-{4-[4-(1-pyrrolidinecarbonyl)benzyl]-phenyl}amino-imidazolinehydrochloride (193 mg, 77%), m.p. shrinks at 46° C.; Analysis forC₂₁H₂₅ClN₄O_(00.7)H₂O: Calc.: C, 63.71; H, 6.69; N, 14.09; Found: C,63.44; H, 6.38; N, 13.81.

[0559] Proceeding as described in Example 13, step 4, but replacingpyrrolidine with other amines, and then correspondingly as in Example13, subsequent steps, other compounds of Formula I were prepared:

[0560] 2-[4-(4-isobutylaminocarbonylbenzyl)-phenyl]amino-imidazolineoxalate, m.p. 100-144° C.; Analysis for C₂₃H₂₈N₄O₅: Calc.: C, 62.71; H,6.41; N, 12.72; Found: C, 62.44; H, 6.36; N, 12.72; and

[0561] 2-[4-(4-benzylaminocarbonylbenzyl)-phenyl]amino-imidazolineoxalate, m.p. 188.5-195.0° C.; Analysis for C₂₄H₂₄N₄O.0.85C₂H₂O₄: Calc.:C, 66.95; H, 5.62; N, 12.15; Found: C, 67.05; H, 5.55; N, 12.26.

Example 142-[4-(4-Cyclopentyloxythien-2-ylmethyl)phenyl]amino-imidazoline

[0562] The following is a preparation of a compound of Formula I fromthe corresponding compound of formula Ih in which R¹ is a grouprepresented by formula (B) where X is S, R² is hydrogen, Y iscyclopentyl, and m is an integer 0.

[0563] Step 1

[0564] To a solution of cyclopentanol (8.75 ml, 95.8 mmol) inN,N-dimethylformamide (250 mL) was added sodium hydride (60% dispersionin mineral oil, 3.84 g, 95.8 mmol) at 0-5° C. under nitrogen. After 10minutes, the mixture was allowed to reach room temperature and stirredfor 40 minutes. 3-Bromothiophene (3.59 mL, 38.3 mmol) was added followedby cuprous iodide (14.63 g, 76.8 mmol). The mixture was heated at 120°C. for 22 hours. After cooling to about 10° C., a solution of sodiumcyanide (12.1 g, 0.25 mol) in water (200 mL) was added under vigorousstirring. The mixture was stirred for additional 10 minutes thenfiltered. The filtrate was extracted with hexane. The extract was washedwith water, dried (Na₂SO₄) and concentrated to dryness. Distillation(100° C., 8 mm Hg) gave 3-cyclopentyloxythiopene (4.52 g, 70%) as aslightly pale yellow oil; ¹H NMR (300 Mz, CDCl₃) δ 7.15 (dd, J=5.2, 3.1Hz, 1H), 6.72 (dd, J=5.2, 15 Hz, 1H) 6.19 (dd, J=3.1, 1.5 Hz, 1H), 4.65(quintet, J=4.2 Hz, 1H), 1.55-1.95 (m, 8H). MS m/e (%): 168 (M+; 17).

[0565] Step 2

[0566] 2-Chloro-3-cyclopentyloxythiophene was prepared according to theprocedures described in P. Stanetty and E. Puschautz, MonatshefteChemie, 1989, 120, 65. Thus, to a solution of 3-cyclopentyloxythiophene(3.98 g, 23.7 mmol) in dichloromethane (35 mL) was added sulfurylchloride (2 mL, 24.9 mmol) at 15° C. under argon. The mixture wasstirred for 1 hour, then concentrated to dryness. Purification by flashchromatography (silica, 100% hexane) gave2-chloro-3-cyclopentyloxythiophene (2.75 g, 59%) as a pale yellow oil;¹HNMR (300 MHz, CDCl₃) δ 6.99 (d, J=6.0 Hz, 1H), 6.75 (d, J=6.0 Hz, 1H),4.69-4.74 (m, 1H), 1.7-1.93 (m, 6H), 1.5-1.7 (m, 2H). MS m/e (%): 202(M+; 6).

[0567] Step 3

[0568] To a solution of 2-chloro-3-cyclopentyloxythiophene (2.15 g, 10.6mmol) in ether (27 mL) was added n-butyllithium (2.5 N in hexanes, 4.4mL, 11 mmol) dropwise at −78° C. under argon. The mixture was allowed toreach 20-25° C. and stirred for 4 hours. After cooling back to −78° C.,a solution of p-nitrobenzaldehyde (1.56 g, 10.3 mmol) in tetrahydrofuran(27 mL) was added dropwise. The mixture was stirred at −78° C. for 1hour. Saturated ammonium chloride was added at −78° C. and the mixturewas allowed to reach about 10° C. The crude product was extracted withethyl acetate, washed with water, brine, dried (Na₂SO₄), andconcentrated to dryness to give4-(5-chloro-4-cyclopentyloxythien-2-yl)-(4-nitrophenyl)methanol (3.6 g),and was directly used in the next step.

[0569] Step 4

[0570] 4-(4-Cyclopentyloxythien-2-ylmethyl)-nitrobenzene may be preparedby methods described in E. J Stoner et al., Tetrahedron, 1995, 51,11043. Thus, to a suspension of sodium iodide (6.64 g, 44.3 mmol) inacetonitrile (10 mL) was added trimethylsilyl chloride (5.6 mL, 44.3mmol) at 20-25° C. under argon. After stirring for 15 minutes at 20-25°C., the mixture was cooled to 0-5° C. and a solution of crude4-(5-chloro-4-cyclopentyloxythien-2-yl)-(4-nitrophenyl)methanol (3.6 g)in acetonitrile (10 mL) was slowly added. Aqueous sodium hydroxide (10%,11.5 mL) was added followed by excess water. The product was extractedwith ethyl acetate, washed with a solution of sodium thiosulfate (4.83g) in water (10 mL), water, brine, dried (Na₂SO₄), and concentrated todryness. Purification by flash chromatography (silica, 98.5:1.5 hexaneethylacetate) gave 4-(4-cyclopentyloxy-thien-2-ylmethyl)-nitrobenzene(1.25 g, 40%) as a pale yellow oil; ¹HNMR (300 MHZ, CDCl₃) δ 11.97 (d,J=8-8, 2H), 7.40 (d, J=8.8 Hz, 2H), 6.45 (m, 1H), 6.03 (d, J=1.7, 1H),4.60 (quintet, J=4.3 Hz, 1H), 4.13 (5, 2H), 1.5-1.89 (m, 8H). MS m/e(%): 303 (M+; 15).

[0571] Step 5

[0572] To a solution of4-(4-cyclopentyloxythien-2-ylmethyl)-nitrobenzene (1.28 g, 4.2 mmol) inabsolute ethanol (34 mL) was added tin dichloride hydrate (4.76 g, 21.2mmol) at 20-25° C. under nitrogen. The mixture was heated at 75° C. for2.5 hours and cooled to 0-5° C. Saturated sodium bicarbonate was addedto pH 8. Ethyl acetate was added and the mixture was filtered. Thelayers were separated, and the aqueous phase was extracted withadditional ethyl acetate. The combined organic phases were washed withbrine, dried (Na₂SO₄), and concentrated to dryness. Purification byflash chromatography (silica, hexane/ethylacetate) gave4-(4-cyclopentyloxythien-2-ylmethyl)-phenylamine (0.47 g, 41%) as a paleyellow oil; ¹H NMR (300 MHz, CDCl₃) δ 7.03 (d, J=8.5 Hz, 2H), 6.63 (d,J=8.5 Hz 2H), 6.41 (m, 1H), 5.96 (d, J=1.7 Hz, 1H, 4.58 (quintet, J=4.3Hz, 1H), 3.91 (S, 2H), 3.59 (bs, 2H), 1.67-1.88 (m, 6H), 1.46-1.67 (m,2N).

[0573] Last Step

[0574] To a solution of 4-(4-cyclopentyloxythien-2-ylmethyl)-phenylamine(463 mg, 1.69 mmol) in isopropyl alcohol (7 ml) was added a solution of2-chloro-2-imidazoline (293 mg, 2.8 mmol) in isopropyl alcohol (7 ml).The mixture was heated at reflux overnight, and the isopropyl alcoholwas removed in vacuo. 10% Sodium hydroxide was added, and the productwas extracted with dichloromethane. The extract was washed with water,dried (Na₂SO₄) and concentrated to dryness to give a crude product.

[0575] The crude product (578 mg) was dissolved in toluene (20 mL), andfollowed by the addition of cyclopentanol (4 mL) and p-toluenesulfonicacid hydrate (674 mg). The mixture was heated at 100-110° C. for 2 hoursand cooled to room temperature. 10% Sodium hydroxide was added. Thefinal product was extracted with dichloromethane (3×), washed withwater, dried (Na₂SO₄), and concentrated to dryness. Purification bypreparative TLC, eluting with ethyl acetate/methyl alcohol/isopropylamine, gave2-[4-(4-cyclopentyloxythien-2-ylmethyl)phenyl]amino-imidazoline (290 mg,50%) as a pale yellow oil; ¹H NMR δ 300 MHz, CDCl₃) δ 7.13 (d, J=8.2 Hz2H), 6.93 (d, J=8.2 Hz 2H), 6.42 (m, 1H), 5.97 (d, J=1.7 HZ, 1H), 4.59(quintet, J=4.3 Hz, 1H), 3.96 (S, 2H), 3.8-4.1 (broad, 2H), 3.52 (S,4H), 1.67-1.89 (m, 6H), 1.51-1.66 (m, 2H).

[0576] 2-[4-(4-cyclopentyloxythien-2-ylmethyl)phenyl]amino-imidazolineoxalate, m.p. 142.4-143.3° C.

[0577] Proceeding as in Example 14, step 1, but replacing cyclopentanolwith isopropanol, and then correspondingly as in Example 14, subsequentsteps, gave 2-[4-(4-isopropoxythien-2-ylmethyl)phenyl]amino-imidazolineoxalate, m.p. 151.3-151.8° C.

Example 15 2-[4-(5-Methoxythien-2-ylmethyl)phenyl]amino-imidazoline

[0578] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ii in which R¹ is agroup represented by formula (B) where X is S, R² is hydrogen, Y ismethyl, and m is an integer 0.

[0579] Step 1

[0580] 2-Methoxythiophene was prepared by the procedures described in H.A. Keeystra et al., Tetrahedron, 1992, 48, 3633. Thus, a solution ofsodium methoxide in methanol was prepared by adding sodium (2.12 g, 92.2mmol) to methanol (14 ml). 2-Bromothiophene (10 g, 61.3 mmol) was addedwhile maintaining reflux. Cuprous bromide (0.88 g, 6.1 mmol) was addedand the mixture was maintained at reflux for 5.5 hours. A solution ofsodium cyanide (3 g, 61.3 mmol) in water (30 ml) was added at 20-25° C.under vigorous stirring. The mixture was stirred until all solidsdissolved, extracted with hexane, dried (Na₂SO₄), and concentrated todryness. Distillation (90° C., 80 mm Hg) gave 2-methoxythiophene (5.35g,-76%) as a colorless oil.

[0581] Step 2

[0582] 5-Methoxythien-2-yl-(tri-n-butyl)stannane was prepared by theaddition n-butyllithium (1.98 M in hexanes, 3.81 mL, 7.54 mmol) to asolution of 2-methoxythiophene (860 mg, 7.54 mmol) in tetrahydrofuran(4.3 mL) at −78° C. under argon. The mixture was allowed to reach 0-5°C. and stirred for 2 hours, re-cooled to −78° C. and tributyltinchloride (2.05 ml, 7.54 mmol) was added. The mixture was allowed toreach 0-5° C. and stirred for 1 hour. The product,5-methoxythien-2-yl-(tri-n-butyl)stannane, was directly used in the nextstep.

[0583] Step 3

[0584] 5-Methoxythien-2-yl-(tri-n-butyl)stannane was added to4-chloromethylphenyl-carbamic acid 2-trimethylsilanyl ethyl ester (2.15g, 7.54 mmol) (described in Preparation 2) at 20-25° C. followed byhexamethylphosphoramide. (11 mL) andtetrakis(triphenylphosphine)-palladium (174.2 mg, 0.146 mmol). Themixture was heated at 65° C. for 4.5 hours. Water was added and productextracted with ether. The extract was washed with water, dried (Na₂SO₄),and concentrated to dryness. The residue was dissolved in acetonitrileand washed twice with hexane. The acetonitrile phase was concentrated todryness, and purification by flash chromatography on silica, elutingwith hexane/ethyl acetate, gave[4-(5-methoxythien-2-ylmethyl)phenyl]-carbamic acid 2-trimethylsilanylethyl ester (690 mg, 25%) as a yellow liquid; ¹H NMR (300 MHz, CDCl₃) δ7.25 (d, J=8.5 Hz 2H), 7.16 (d, J=8.5 Hz 2H), 6.49 (bs, 1H), 6.37 (dt,J=3.7, 1.0 Hz, 1H), 5.98 (d, J=3.7, 1H), 4.25 (m, 2H), 3.94 (bs, 2H),3.82 (s, 3H), 1.04 (m, 2H), 0 06 (s, 9H).

[0585] Step 4

[0586] To a solution of [4-(5-methoxythien-2-ylmethyl)phenyl]-carbamicacid 2-trimethylsilanyl ethyl ester (684 mg, 1.88 mmol) in dimethylsulfoxide (24 mL) was added tetra-n-butylammonium fluoride (1 M intetrahydrofuran, 5.6 mL) at 20-25° C. under argon. The mixture wasstirred for 1 hour. Ether was added and the solution was washed withwater, brine, dried (Na₂SO₄), and concentrated to dryness. Purificationby flash chromatography on silica, eluting with hexane/ethyl acetate,gave 4-(5-methoxythien-2-ylmethyl)-phenylamine (372 mg, 90%) as a thickyellow oil; ¹H NMR (300 MHz, CDCl₃) δ 7.02 (d, J=8.5 Hz, 2H), 6.63 (d,J=8.5 Hz, 2H), 6.36 (dt, J=3.7, 1.1 Hz, 1H), 5.97 (d, J=3.7 Hz, 1H),3.87 (bs, 2H), 3.81 (5, 3H), 3.4-3.7 (broad, 1H). MS m/e (%): 219 (M+;100).

[0587] Last Step

[0588] To a solution of [4-(5-methoxythien-2-ylmethyl)-phenylamine (145mg, 0.66 mmol) in acetonitrile (10 ml) was added 2-chloro-2-imidazolinesulfate (155 mg, 0.76 mmol) at 20-25° C. under nitrogen. The resultingsuspension was heated at 80° C. for 1.5 hours. The mixture was dilutedwith dichloromethane and washed with 10% sodium hydroxide, water, dried(Na₂SO₄), and concentrated to dryness. Purification by preparative TLC,eluting with ethyl acetate/methyl alcohol/isopropylamine, gave2-[4-(5-methoxythien-2-ylmethyl)phenyl]amino-imidazoline (132 mg, 70%)as a yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 7.12 (d, J=8.4 Hz, 2H), 6.93(d, J=8.4 Hz, 2H), 6.39 (dt, J=3.7, 1.1 Hz, 1H), 5.98 (d, J=3.7 Hz, 1H),3.92 (bs, 2H), 3.82 (S, 3H), 3.52 (S, 4H), 3.15-3.35 (broad, 2H).

[0589] 2-[4-(5-methoxythien-2-ylmethyl)phenyl]amino-imidazoline oxalate,m.p. 121.8-122.8° C.

Example 162-[4-(5-Cyclopentyloxythien-2-ylmethyl)phenyl]amino-imidazoline

[0590] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ii in which R¹ is agroup represented by formula (B) where X is S, R² is hydrogen, Y iscyclopentyl, and m is an integer 0.

[0591] To a mixture of cyclopentanol (51.1 ml, 0.56 mol) and dioxane (50mL) was added sodium hydride (60% in mineral oil, 4.91 g, 0.12 mol) at0-5° C. under argon. The mixture was heated at 80° C. until anhomogenous solution was observed. 2-Bromothiophene (10 g, 5.9 mL, 0.061mol) was added at 80° C., followed by cuprous iodide (11.7 g, 0.061mol). The mixture was heated at 120° C. for 6 hours. After cooling to20-25° C., sodium cyanide (30 g, 0.61 mol) in water (200 mL) was added.The mixture was vigorously stirred for 20 minutes, filtered, andextracted with hexane. The hexane extract was washed with water, dried(Na₂SO₄), and concentrated to dryness. Filtration through a column(silica, 100% hexane) gave 2-cyclopentyloxythiophene (2.6 g, 25.2%) as acolorless oil; ¹HNMR (300 MHz, CDCl₃) δ 6.7 (dd, J=5.7, 3.7 Hz, 1H),6.54 (dd, J=5.7, 1.5 Hz, 1H), 86.18 (dd, J=3.7, 1.5 Hz, 1H) 4.66 (Sept,J=2.7 Hz, 1H), 1.5-2.0 (m, 8H).

[0592] Proceeding as described in Example 15, step 2, but replacing2-methoxythiophene with 2-cyclopentyloxythiophene, and thencorrespondingly as in Example 15, subsequent steps gave2-[4-(5-cyclopentyloxythien-2-ylmethyl)phenyl]amino-imidazoline oxalate,m.p. 71.2-75.5° C.

Example 17 2-[4-(5-Isopropoxythien-2-ylmethyl)phenyl]amino-imidazoline

[0593] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ii in which R¹ is agroup represented by formula (B) where X is S, R² is hydrogen, Y isisopropyl, and m is an integer 0.

[0594] To a solution of 4-(5-methoxythien-2-ylmethyl)-phenylamine (210mg, 0.96 mmol) in isopropyl alcohol (20 ml) was added p-toluenesulfonicacid hydrate (460 mg, 2.4 mmol) under nitrogen. The mixture was heatedat reflux for 24 hours and cooled to 20-25° C. 5% Sodium hydroxide wasadded, and the product was extracted with dichloromethane. The extractwas dried (Na₂SO₄), and concentrated to dryness. Purification bypreparative TLC, eluting with hexane/ethyl acetate, gave4-(5-isopropoxythien-2-ylmethyl)-phenylamine (135 mg, 57%) as a paleyellow oil; ¹HNMR (300 MHz, CDCl₃) δ 7.02 (d, J=8.5 Hz, 2H), 6.63 (d,J=8.5 Hz, 2H), 6.34 (dt, J=3.7, 1.1 Hz, 1H), 6.01 (d, J=3.7, 1H), 4.26(quintet, J=6.1 Hz, 1H), 3.88 (bs, 2H), 1.31 (d, J=6.1 Hz, 6H). MS m/e(%): 247 (M⁺; 58).

[0595] Last Step

[0596] To a solution of 4-(5-isopropoxythien-2-ylmethyl)-phenylamine(131 mg, 0.53 mmol) in aceonitrile (8 ml) was added2-chloro-2-imidazoline sulfate (121 mg, 0.59 mmol) at 20-25° C. underargon. The mixture was heated at 800 C for 1.5 hours. The mixture wasdiluted with dichloromethane and washed with sodium hydroxide, water,dried (Na₂SO₄) and concentrated to dryness. Purification by preparativeTLC, eluting with ethyl acetate/methyl alcohol/isopropylamine, gave2-[4-(5-isopropoxythien-2-ylmethyl)phenyl]amino-imidazoline (150 mg,90%) as a thick yellow oil; ¹H NMR (300 Mhz, CDCl₃ δ 7.13 (d, J=8.4 Hz,2H) 6.93 (d, J=8.4 Hz, 2H), 6.37 (dt, J=3.7, 1.0 Hz, 1H), 6.02 (d, J=3.7Hz, 1H), 4.28 (quintet, J=6.2 Hz, 1H), 3.93 (bs, 2H), 3.52 (5, 4H),3.24-3.5 (broad, 2H), 1.32 (d, J=6.2 Hz, 6H). MS m/e (%):316 (M+1,100%).

[0597] 2-[4-(5-isopropoxythien-2-ylmethyl)phenyl]amino-imidazolineoxalate, m.p. 134.4-135° C.

Example 182-[4-(1-Isopropylaminocarbonylpiperidin-1-ylmethyl)-phenyl]amino-imidazoline

[0598] The following is a preparation of a compound of Formula I fromthe corresponding compound of formula Ij in which R¹ is a grouprepresented by formula (C) where X is N, R², R⁴, and R⁸ are hydrogen, R⁹is isopropyl, V is 0, and m is an integer 0.

[0599] Step 1

[0600] A mixture of 4-(4-nitrobenzyl)pyridine (12.85 g, 60 mmol),platinum(IV) oxide (1.0 g), 12N hydrochloric acid (5 ml, 60 mmol), water(5 ml) in ethanol (200 ml) was hydrogenated at 40 psi in a Parrapparatus for 12 hours. The reaction mixture was concentrated in vacuo,and the residue was diluted with cold water and basified with 10% sodiumhydroxide solution. The resulting mixture was extracted into ethylacetate. The combined organic extracts were washed with water and brine,dried (Na₂SO₄), and concentrated in vacuo. The residue oncrystallization from ethyl acetate/hexanes gave4-(piperidin-4-ylmethyl)-phenylamine (9.85 g, 86%) as a whitecrystalline solid, m.p. 110-113° C.

[0601] Step 2

[0602] A solution of 4-(piperidin-4-ylmethyl)-phenylamine (0.57 g, 3mmol) in dicholoromethane (20 mL) was cooled in an ice bath undernitrogen atmosphere. Isopropyl isocyanate (0.28 g, 3.3 mmol) was addeddropwise to the solution and stirred at ice bath temperature for 30minutes. The reaction mixture was quenched with water and extracted withdichloromethane. The combined organic extracts were washed with waterand brine, dried, and solvents removed in vacuo. The crude product waschromatographed on silica gel, eluting with 2% methanol/dichloromethanecontaining 0.01% ammonium hydroxide, to give4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenylamine (0.66 g,80%) as a gum.

[0603] Last Step

[0604] A mixture of4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenylamine (0.64 g,2.31 mmol) and 2-chloro-2-imidazoline sulfate (0.70 g, 3.47 mmol) in2-propanol (20 mL) was heated under reflux for 30 minutes. The reactionmixture was concentrated in vacuo. The residue was diluted with water,basified with 10% sodium hydroxide solution and extracted intodichloromethane. The organic layer was washed with water and brine,dried (Na₂SO₄), and concentrated in vacuo. The crude product waschromatographed on neutral aluminum oxide, eluting with 5%methanol/dichloromethane, and crystallized from ethyl acetate containingsome ethanol, to give2-[4-(1-isopropylaminocarbonylpiperidin-4-ylmethyl)-phenyl]amino-imidazoline(0.47 g, 59%) as a white solid, m.p. 191-192° C.

[0605] Proceeding as described in Example 18, step 1, and proceedingdirectly to the last step, gave2-[4-(piperidin-4-ylmethyl)phenyl]amino-imidazoline hydrochloride as afoam.

[0606] Proceeding as described in Example 18, step 2, but replacingisopropyl isocyanate with other isocyanates, and then correspondingly asin Example 15, last step, other compounds of Formula I were prepared:

[0607]2-[4-(1-phenylaminocarbonylpiperidin-4-ylmethyl)phenyl]amino-imidazolinehydrochloride, m.p. shrinks at 99° C. (highly hygroscopic), C₂₂H₂₈N₅OCl;and

[0608]2-[4-(1-ethylaminocarbonylpiperidin-4-ylmethyl)phenyl-}amino-imidazolinehydrochloride, m.p. shrinks at 97° C. (very hygroscopic), C₁₈H₂₈N₅OCl.

Example 192-[4-(1-Benzenesulfonylpiperidin-4-ylmethyl)-phenyl]amino-imidazoline

[0609] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Ik in which R¹ is agroup represented by formula (C) where X is N, R² and R⁴ are hydrogen,and R⁹ is benzene

[0610] Step 1

[0611] A solution of 4-(piperidin-4-ylmethyl)-phenylamine (7.5 g, 39.44mmol) in dry tetrahydrofuran (200 mL) was cooled in an ice bath undernitrogen atmosphere. Di-tert-butyl dicarbonate (9.76 g) was added to thesolution in portions and stirred for 30 minutes. The resulting mixturewas quenched with water, concentrated in vacuo, and extracted with ethylacetate. The organic layer was washed with water and brine, dried, andsolvents removed in vacuo. The crude product was chromatographed on ashort silica gel column, eluting with 30% ethyl acetate/hexanes, to give4-[1-(N-tert-butoxycarbonyl)piperidin-4-ylmethyl]-phenylamine (9.25 g,81%) as an oil which solidifies, m.p. 91-92° C.

[0612] Step 2

[0613] A solution of4-(1-(N-tert-butoxycarbonyl)piperidin-4-ylmethyl]-phenylamine (3.55 g,12.24 mmol) and triethylamine (10.2 mL, 73.4 mmol) in dichloromethane(70 mL) was cooled in an ice bath under nitrogen atmosphere.Trifluoroacetic anhydride (5.2 mL, 36.7 mmol) was added dropwise to thesolution. The resulting mixture was stirred for 30 minutes, quenchedwith pH 7.0 phosphate buffer (100 mL) and methanol (150 mL), and stirredat room temperature for 15 minutes. The reaction mixture wasconcentrated in vacuo, and the residue extracted into ethyl acetate. Theorganic layer was washed with cold water and brine, dried, and solventsremoved in vacuo. The crude product was chromatographed on silica gel,eluting with 30% ethyl acetate/hexanes, to give2,2,2-trifluoro-N-{4-[1-(N-tert-butoxycarbonyl)-piperidin-4-ylmethyl]-phenyl}acetamide(4.43 g, 94%) as a solid, m.p. 145-146° C.; Analysis for C₁₉H₂₅N₂O₃F₃:Calc.: C, 59.06; H, 6.52; N, 7.25; Found: C, 59.40; H, 6.54; N, 7.42.

[0614] Step 3

[0615] A mixture of2,2,2-trifluoro-N-{4-[1-(N-tert-butoxycarbonyl)piperidin-4-ylmethyl]-phenyl}acetamide(3.3 g) and trifluoroacetic acid (5 mL) in dichloromethane (30 mL) wasstirrred at room temperature for 2 hours. The reaction mixture wasdiluted with dichloromethane and cold water, and neutralized with sodiumbicarbonate solution. The organic layer was separated, washed with waterand brine, dried, and solvents removed in vacuo to give2,2,2-trifluoro-N-[4-(piperidin-4-ylmethyl)-phenyl]acetamide (1.5 g) asa foam.

[0616] Step 4

[0617] A mixture of2,2,2-trifluoro-N-[4-(piperidin-4-ylmethyl)-phenyl]acetamide (0.5 g,1.75 mmol) and triethylamine (0.23 g, 2.1 mmol) in dichloromethane (10mL) was cooled in an ice bath under nitrogen atmosphere. A solution ofbenzenesulfonyl chloride (0.37 g, 2.1 mmol.) in dichloromethane (1 mL)was added under to the mixture while stirring. After 2 hours, thereaction mixture was quenched with water. The separated organic layerwas washed with cold water and brine, dried, and solvents removed invacuo. The residue was crystallized from ethyl acetate/hexanes to give2,2,2-trifluoro-N-[4-(1-benzenesulfonyl-piperidin-4-ylmethyl)-phenyl]acetamide(0.43 g, 57%), m.p. 194-195° C.; Analysis for C₂₀H₂₁N₂O₃SF₃: Calc.: C,56.32; H, 4.96; N, 6.57; Found: C, 56.54; H, 4.99; N, 6.68.

[0618] Step 5

[0619] A mixture of2,2,2-trifluoro-N-[4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenyl]acetamide(0.45 g) and lithium hydroxide (0.23 g) in methanol (10 mL) and water (1mL) was stirred for about 48 hours. The reaction mixture wasconcentrated in vacuo, diluted with cold water, and extracted withdichloromethane. The organic layer was washed with cold water and brine,dried, and solvents removed in vacuo. The residue was crystallized fromethyl acetate/hexanes to give4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenylamine (0.29 g, 83%),m.p. 158° C.; Analysis for C₁₈H₂₂N₂O₂S: Calc.: C, 65.43; H, 6.71; N,8.48; Found: C, 65.59; H, 6.61; N, 8.66.

[0620] Last Step

[0621] A mixture of4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenylamine (0.28 g, 0.83mmol) and 2-chloro-2-imidazoline sulfate (0.25 g, 1.25 mmol) in2-propanol (20 mL) was heated under reflux for 30 minutes under nitrogenatmosphere. The reaction mixture was concentrated in vacuo. The residuewas basified with 10% sodium hydroxide solution and extracted withdichloromethane. The organic layer was washed with cold water and brine,dried, and solvents removed in vacuo. The residue was chromatographed onneutral aluminum oxide, eluting with 1% methanol/dichloromethane, togive2-[4-(1-benzenesulfonylpiperidin-4-ylmethyl)-phenyl]amino-imidazoline(0.29 g, 89%) as a foam. Analysis for C₂₁H₂₆N₄O₂S.5H₂O: Calc.: C, 61.89;H, 6.68; N, 13.75; Found: C, 62.00; H, 6.52; N, 13.85.

[0622] Proceeding as described in Example 19, step 4, but replacingbenzenesulfonyl chloride with other sulfonyl chlorides or carbonylchlorides, and then correspondingly as in Example 19, subsequent steps,other compounds of Formula I were prepared:

[0623]2-[4-(1-methanesulfonylpiperidin-4-ylmethyl)phenyl]amino-imidazolinehydrochloride; Analysis for C₁₆H₂₅N₄O₂ClS;

[0624]2-[4-(1-isopropylsulfonylpiperidin-4-ylmethyl)phenyl]amino-imidazoline;Analysis for C₁₈H₂₈N₄O₂S.4H₂O: Calc.: C, 58.16; H, 7.81; N, 15.07;Found: C, 58.26; H, 7.52; N, 14.96;

[0625]2-[4-(1-isopropylcarbonylpiperidin-4-ylmethyl)phenyl]amino-imidazoline,m.p. 193-194° C.; Analysis for C₁₉H₂₈N₄O: Calc.: C, 69.48; H, 8.59; N,17.06; Found: C, 69.41; H, 8.59; N, 16.95;

[0626]2-[4-(1-isobutylcarbonylpiperidin-4-ylmethyl)phenyl]amino-imidazoline,m.p. 122-125° C.; MS m/z, 343(M+1); and

[0627]2-{4-[1-(3-methylbutylcarbonyl)piperidin-4-ylmethyl]phenyl}amino-imidazolinehydrochloride, m.p. 155-157° C.; Analysis for C₂₁H₃₃N₄OCl: Calc.: C,64.19; H, 8.46; N, 14.26; Found: C, 64.05; H, 8.39; N, 14.27.

Example 202-{4-[1-(1-Piperidinesulfonyl)piperidin-4-ylmethyl]-phenyl}amino-imidazoline

[0628] The following is an alternative preparation of a compound ofFormula I from the corresponding compound of formula Il in which R¹ is agroup represented by formula (C) where X is N, R² and R⁴ are hydrogen,and R⁸ and R⁹ together with the nitrogen to which they are attached formpiperidine.

[0629] Step 4

[0630] A solution of2,2,2-trifluoro-N-[4-(piperidin-4-ylmethyl)-phenyl]acetamide (0.5 g,1.75 mmol) (prepared as previously described in Example 19, steps 1 to3) and triethylamine in dichloromethane (10 mL) was cooled in an icebath under a nitrogen atmosphere. The mixture was then treated with asolution of 1-piperidinesulfonyl chloride (0.39 g, 2.09 mmol) indichloromethane (1 mL). The reaction mixture was stirred for 1.5 hoursat 0-5° C. and quenched with water. The organic layer was separated, andthe aqueous layer extracted with dichloromethane. The combined organicextracts were washed with water and brine, dried, and solvents removedin vacuo. The residue was chromatographed on silica gel, eluting with30% ethyl acetate/hexanes, to give2,2,2-trifluoro-N-[4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenyl]acetamide(0.48 g) as a white solid, m.p. 156-157° C.; Analysis for C₁₉H₂₆N₃O₃SF₃:Calc.: C, 52.64; H, 6.05; N, 9.69; Found: C, 52.84; H, 6.00; N, 9.79.

[0631] Step 5

[0632] A mixture of2,2,2-trifluoro-N-[4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenyl]acetamide(0.48 g, 1.11 mmol) and lithium hydroxide (0.23 g, 5.54 mmol) inmethanol (10 mL) and water (1 mL) was heated at 60° C. for about 2hours. The reaction mixture was concentrated in vacuo, diluted withwater, and extracted with dichloromethane. The organic extracts werewashed with water and brine, and dried (Na₂SO₄). The residue wascrystallized from ethyl acetate/hexanes, to give4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenylamine (0.30 g) as awhite solid, m.p. 144-145° C.; Analysis for C₁₇H₂₇N₃O₂S: Calc.: C,60.50; H, 8.06; N, 12.45; Found: C, 60.76; H, 8.07; N, 12.56.

[0633] Last Step

[0634] Proceeding as previously described in Example 19, last step, gave2-[4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenyl]amino-imidazoline(0.29 g, 89%) as a foam. Analysis for C₂₀H₃₁N₅O₂S: Calc.: C, 59.23; H,7.70; N, 17.27; Found: C, 59.13; H, 7.56; N, 17.13.

[0635] Proceeding as in Example 20, step 4, but replacing1-piperidinesulfonyl chloride with 1-pyrrolidinesulfonyl chloride, andcorrespondingly as in Example 20, subsequent steps, gave2-[4-(1-pyrrolidinesulfonylpiperidin-4-ylmethyl)-phenyl]amino-imidazolineas a foam; Analysis for C₁₉H₂₉N₅O₂S: Calc.: C, 57.23; H, 7.53; N, 17.56;Found: C, 57.27; H, 7.24; N, 17.40.

Example 21 X-Ray Diffraction Patterns of Crystal Form I

[0636] Crystal Form I of2-[4-(4-Isopropoxybenzyl)phenyl]-amino-imidazoline sulfate is preparedby methods previously described in Example 1. The X-ray diffractionpattern shown in FIG. 1 was obtained utilizing a Scintag X1 powder X-raydiffractometer equipped with a copper Kα1 irradiation source. Thenumbers indicated in FIG. 1, top and lower abcissae indicate “d” spacingand 20, respectively; and right and left ordinates indicate relativeintensities in % and counts per second (CPS), respectively.

[0637] The X-ray powder diffraction patterns given below are in terms of‘d’-spacings and relative intensities (RI) above 3%. The weighted meanvalue of X-ray wavelength used for the calculations was 1.5406 10¹⁰ cm.d, 10⁻¹⁰ m RI, % d, 10⁻¹⁰ m RI, % 31.084 100 4.391 3 10.266 4 4.179 97.686 39 4.149 9 5.546 4 3.947 7 5.451 3 3.898 6 5.118 10 3.838 4 4.83810 3.697 6 4.767 13 3.554 3 4.744 13 3.408 3

Example 22 Preparation of Crystal Form II

[0638] 2-[4-(4-Isoproxybenzyl)phenyl]amino-imidazoline sulfate(194 mg)was dissolved in water (1 mL) at 60° C., and the clear supernatant wastransferred into a Craig tube and cooled in an ice-water bath. Crystalswere collected by centrifugation and dried under vacuum at ambienttemperature to give Crystal Form II of2-[4-(4-isopropoxybenzyl)phenyl]-amino-imidazoline sulfate (138 mg),m.p. 217-218° C.

[0639] Alternatively, 2-[4-(4-isoproxybenzyl)phenyl]amino-imidazolinesulfate(38 g) was dissolved in water (500 mL) at 80° C. After hotfiltration, the solution was cooled to ambient temperature and stored at4° C. for 5 hours. Crystals were collected by filtration and dried atambient temperature to give Crystal Form II of2-[4-(4-isopropoxy-benzyl)phenyl]-amino-imidazoline sulfate (33.6 g),m.p. 216-217° C.

Example 23 X-Ray Diffraction Patterns of Crystal Form II

[0640] The X-ray diffraction pattern of Crystal Form II shown in FIG. 2was obtained utilizing a Scintag X1 powder X-ray diffractometer equippedwith a copper Kα1 irradiation source. The numbers indicated in FIG. 1,top and lower abcissae indicate “d” spacing and 20, respectively; andright and left ordinates indicate relative intensities in % and countsper second (CPS), respectively.

[0641] The X-ray powder diffraction patterns given below are in terms of‘d’ spacings and relative intensities (RI) above 3%. The weighted meanvalue of X-ray wavelength used for the calculations was 1.5406 10⁻¹⁰ cm.d, 10⁻¹⁰ m RI, % d, 10⁻¹⁰ m RI, % 25.664 100 4.258 9 12.756 3 4.086 36.386 49 3.910 4 4.397 7 3.307 4

Example 24

[0642] Composition for Oral Administration The composition contains: %wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesium stearate 0.5%

[0643] The two ingredients are mixed and dispensed into capsulescontaining 100 mg each; one capsule would approximate a total dailydosage.

Example 25

[0644] Composition for Oral Administration The composition contains: %wt./wt. Active ingredient 20.0% Magnesium stearate 0.5% Crosscarmellosesodium 2.0% Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%

[0645] The above ingredients are combined and granulated using methanolas solvent. The formulation is then dried and formed into tablets(containing 20 mg of active compound) with an appropriate tabletingmachine.

Example 26

[0646] Parenteral Formulation (IV) The composition contains: % wt./wt.Active ingredient. 0.25 g Sodium Chloride qs to make isotonic Water forinjection to 100 ml

[0647] The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Example 27

[0648] Suppository Formulation The composition contains: % wt./wt.Active ingredient 1.0% Polyethylene glycol 1000 74.5% Polyethyleneglycol 4000 24.5%

[0649] The ingredients are melted together and mixed on a steam bath,and poured into molds containing 2.5 g total weight.

Example 28

[0650] Topical Formulation Ingredients grams Active compound 0.2-2  Span 60 2 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

[0651] All of the above ingredients, except water, are combined andheated to 60° C. with stirring. A sufficient quantity of water at 60° C.is then added with vigorous stirring to emulsify the ingredients, andwater then added q.s. 100 g.

Example 29 Nasal Spray Formulations

[0652] Several aqueous suspensions containing from 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such asmicrocrystalline cellulose, sodium carboxymethylcellulose, dextrose, andthe like. Hydrochloric acid may be added to adjust pH. The nasal sprayformulations may be delivered via a nasal spray metered pump typicallydelivering 50-100 microliters of formulation per actuation. A typicaldosing schedule is 2-4 sprays every 4-12 hours.

Example 30 Carrageenan-Induced Mechanical Hyperalgesia Assay

[0653] The anti-inflammatory/analgesic activity of compounds of thisinvention was determined by the Carrageenan-Induced MechanicalHyperalgesia Assay by measuring the inhibition of carrageenan-inducedpaw hyperalgesia in the rat, using a modification of the methoddescribed in L. O. Randall and J. J. Selitto, Archives of InternationalPharmacodynamics, 1957, 11, 409-419, and Vinegar et al., Journal ofPharmacology and Experimental Therapeutics, 1969, 166, 96-103.

[0654] Male Sprague-Dawley rats (130-150 g) were weighed and randomlyassigned to treatment groups (n=10). To induce mechanical hyperalgesia,rats were lightly anesthetized with halothane and administered 1%carrageenan or vehicle 1 (100 μl) in the plantar surface of the lefthindpaw. Rats were administered vehicle (10 ml/kg, p.o. or 1 ml/kg, i.v)or compounds of this invention (at 1, 3, 10, 30 and 100 mg/kg, p.o.) or(0.3, 1.0, 3.0 and 10 mg/kg, i.v.) one hour before testing. Mechanicalhyperalgesia was measured using an Analgesy-meter (UGO BASILE,Biological Research Apparatus, Comerio, Italy). The vehicle- orcarrageenan-treated hindpaw was placed on the dome of the apparatus,plantar surface facing down. A constantly increasing force was thenapplied to the dorsal surface of the paw. The force at which the ratwithdrew its paw, struggled, or vocalized was considered the end point.

[0655] Treatment groups were compared using a one-way analysis ofvariance on the paw withdrawal force (RESP). Pairwise comparisons forthe drug-treated groups to the vehicle group were made using Fisher'sLSD strategy and Dunn's procedure. Percent inhibition of mechanicalhyperalgesia was calculated for each animal, and the average ID₅₀ valuewas estimated using the following sigmoidal model:

% inhibition=100/(1+exp((ID ₅₀−dose)/N))

[0656] where ID₅₀ is the dose of the compound needed to inhibit half ofthe maximum response (i.e., 100% in this model) and N is a curvatureparameter.

[0657] The compounds of this invention were active in this assay.

Example 31 Complete Freund's Adjuvant-Induced Mechanical HyperalgesiaAssay

[0658] The anti-inflammatory/analgesic activity of compounds of thisinvention may also be determined using an adjuvant-induced arthritispain model in the rat, where pain is assessed by the animal's responseto the squeezing of the inflamed foot, using a modification of themethod described in J. Hylden et al., Pain 1989, 37, 229-243. Themodification includes the assessment of hyperalgesia instead of changesin activity of spinal cord neurons.

[0659] Briefly, rats were weighed and randomly assigned to treatmentgroups. To induce mechanical hyperalgesia, rats were lightlyanesthetized with halothane and 100 μl of Complete Freund's Adjuvant orsaline was administered into the plantar surface of the left hindpaw.Twenty-four hours later, water (vehicle) or compounds of this inventionwere orally administered to the rats one hour before testing. Mechanicalhyperalgesia was measured using an Analgesy-meter (UGO BASILE,Biological Research Apparatus, Comerio, Italy). The saline orcarrageenan-treated hindpaw was placed on the dome of the apparatus,plantar surface facing down. A constantly increasing force was thenapplied to the dorsal surface of the paw, and the force at which the ratwithdrew its paw, struggled, or vocalized was considered the end point.The treatment groups were compared using a one-way analysis of varianceon the paw withdrawal force. Percent inhibition was calculated for eachanimal in the form:

100×((c/d−c/v)÷(s/v−c/v))

[0660] where c/d is the paw withdrawal force for the carrageenan-treatedpaw in an animal to which drug has been administered; c/v is the pawwithdrawal force for the carrageenan-treated paw in an animal to whichvehicle has been administered; and s/v is the paw withdrawal force forthe saline-treated paw in an animal to which vehicle has beenadministered. Significance was determined using Student's t-test.

[0661] The compounds of the invention were active in this assay.

Example 32 Inhibition of Bladder Contractions Induced by IsovolumetricBladder Distension in Rats

[0662] The inhibition of bladder contractions was determined by an assayusing a modification of the method described in C. A. Maggi et al., J.Pharm. and Exper. Therapeutics, 1984, 230, 500-513.

[0663] Briefly, male Sprague-Dawley rats (200-250 g) were weighed andrandomly assigned to treatment groups. A catheter was inserted throughthe urethra into the bladder to induce bladder contractions, and a warmsaline solution (5 mL) was infused. Rhythmic contractions were producedin about 30% of the animals. The compounds of the invention (0.1, 0.3 or1 mg/kg) were administered intravenous at the onset of regular rhythmiccontractions. The effects on rhythmic contracts were then measured.

[0664] The compounds of this invention were active in this assay.

Example 33 Inhibition of Volume-Induced Contractions in Rats

[0665] The inhibition of bladder contractions was determined by an assayusing a modification of the method described in S. S. Hegde et al.,Proceedings of the 26th Annual Meeting of the International ContinenceSociety (August 27th-30th) 1996, Abstract 126.

[0666] Female Sprague-Dawley rats were anesthetized with urethane andinstrumented for intravenous administration of drugs and, in some cases,measurement of arterial pressure, heart rate and intra-bladder pressure.The effect of test compounds on volume-induced bladder contractions wasdetermined in separate groups of animals. Volume-induced reflex bladdercontractions were induced by filling the bladder with saline. The testcompounds were administered intravenously in a cumulative manner at10-minute intervals. Atropine (0.3 mg/kg, iv) was administered at theend of the study as a postive control.

[0667] The compounds of this invention were active in this assay.

Example 34 Reversal of Endotoxin-Induced Hypotension in Rats

[0668] Septic shock, sometimes referred to as endotoxic shock, is causedby the presence of infectious agents, particularly bacterial endotoxins,in the bloodstream and is characterized by hypotension and organdysfunction. Many symptoms of septic shock, in particular, hypotension,are induced in the rat by the administration of bacterial endotoxins.The ability of a compound to inhibit endotoxin-induced hypotension istherefore predictive of the utility of the compound in the treatment ofseptic or endotoxic shock.

[0669] The activity of the compounds of the invention in the treatmentof septic or endotoxic shock was determined by measuring the reversal ofendotoxin-induced hypotension in the rat, using a modification of themethod described in M. Giral et al., British Journal of Pharmacology,1969, 118, 1223-1231.

[0670] Briefly, adult rats (>200 g) were anesthetized with an inhalationanesthetic and femoral arteries and veins were cannulated for insertionof blood pressure transducers and drug administration lines,respectively. They were placed in Mayo restrainers while still under theinfluence of the anesthetic. After recovery from anesthesia andstabilization of heart rate and blood pressure (which typically requiredabout 30 minutes), endotoxin (50 mg/kg E. coli and 25 mg/kg Salmonella)was administered intravenously. Changes in blood pressure and heart ratewere monitored. After one hour, compounds of this invention or vehiclewere also administered intravenously, and cardiovascular parameters werecontinuously monitored for the next three hours. Responses arerepresented as percentage return to initial diastolic blood pressure.Significance was determined using Student's t-test.

[0671] The compounds of this invention were active in this assay.

[0672] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound selected from the group of compoundsrepresented by Formula I:

wherein: R¹ is a group represented by formula (A), (B) or (C):

wherein: X is independently in each occurrence S, O or N; R² and R⁴ areeach independently in each occurrence: (1) hydrogen, (2) alkyloxy, or(3) halogen; R³ is independently in each occurrence: (1) alkyl, (2)cycloalkyl, (3) halogen, (4) heterocyclyl, (5) —NR⁸R⁹, (6)—(CH₂)_(m)CONR⁸R⁹, wherein m is an integer from 0 to 3, (7)(CH₂)_(m)SO₂NR⁸R⁹, wherein m is an integer from 0 to 3, (8)—(CH₂)_(m)NR⁸COR⁹, wherein m is an integer from 0 to 3, (9)—(CH₂)_(m)NR⁷SO₂R⁹, wherein m is an integer from 0 to 3, (10)—(CH₂)_(m)NR⁷C(V)NR⁸R⁹, wherein V is S or O, and m is an integer from 0to 3, (11) —(CH₂)_(m)OY wherein m is an integer from 0 to 3, and Y is:hydrogen, alkyl, alkyloxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl,heterocyclyl, or carboxyalkyl, or (12) —O(CH₂)_(n)Z wherein n is aninteger from 1 to 4 and Z is: cycloalkyl, hydroxyalkyl, cycloalkyloxy,heterocyclyl, aryloxy, heteroaryl, —COR⁹, —CONR⁸R⁹, —SO₂R⁹, —SO₂NR⁸R⁹,or —NR⁷SO₂R⁹, or unsubstituted aryl or mono-, di-, or tri-substitutedaryl, the substituents being independently selected from alkyl, halogen,or alkyloxy; R⁵ is independently in each occurrence: (1) —(CH₂)_(m)OYwherein m is an integer from 0 to 3, and Y is: hydrogen, alkyl,alkyloxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, heterocyclyl, orcarboxyalkyl; or (2) —O(CH₂)_(n)Z wherein n is an integer from 1 to 4and Z is: cycloalkyl, hydroxyalkyl, cycloalkyloxy, heterocyclyl,aryloxy, heteroaryl, —COR⁹, —CONR⁸R⁹, —SO₂R⁹, —SO₂NR⁸R⁹, or —NR⁷SO₂R⁹,or unsubstituted aryl or mono-, di-, or tri-substituted aryl, thesubstituents being independently selected from alkyl, halogen, oralkyloxy; R⁶ is independently in each occurrence: (1) hydrogen, (2)—COR⁹, (3) —CONR⁸R⁹, (4) —C(V)NR⁸R⁹ wherein V is O or S, (5) —SO₂R⁹, or(6) —SO₂NR⁸R⁹; R⁷ and R⁸ are each independently in each occurrence: (1)hydrogen, (2) alkyl, or (3) hydroxyalkyl; R⁹ is independently in eachoccurrence: (1) alkyl, (2) cycloalkyl, (3) arylalkyl, (4) hydroxyalkyl,(5) haloalkyl, (6) heterocyclyl, (7) unsubstituted aryl or mono-, di-,or tri-substituted aryl, the substituents being independently selectedfrom alkyl, halogen, or alkyloxy, or (8) heteroaryl; or R⁸ and R⁹ aretaken together with the nitrogen to which they are attached to form a 5-or 6-membered monocyclic saturated or unsaturated ring, and in which thering is optionally substituted or unsubstituted with oxo; or R⁷ and R⁹are taken together with the nitrogen to which they are attached to forma 5- or 6-membered monocyclic saturated or unsaturated ring, and inwhich the ring is optionally substituted or unsubstituted with oxo; or apharmaceutically acceptable salt or a crystal form thereof.
 2. Thecompound of claim 1 wherein R² and R⁴ are each independently in eachoccurrence hydrogen or halogen.
 3. The compound of claim 2 wherein R²and R⁴ are each independently hydrogen, fluoro or chloro.
 4. Thecompound of claim 3 where R¹ is a group represented by formula (A). 5.The compound of claim 4 wherein R³ is —(CH₂)_(m)OY wherein m is aninteger from 0 to
 3. 6. The compound of claim 5 wherein Y is alkyl,alkyloxyalkyl, cycloalkyl or heterocyclyl.
 7. The compound of claim 6wherein Y is methyl, isopropyl, isobuty, sec-butyl, tert-butyl,alkyloxyalkyl, cycloalkyl or heterocyclyl.
 8. The compound of claim 6wherein Y is alkyl, 2-ethoxy-1-(ethoxymethyl)ethyl, cycloalkyl orheterocyclyl.
 9. The compound of claim 6 wherein Y is alkyl,alkyloxyalkyl, cyclopentyl, cyclohexyl or heterocyclyl.
 10. The compoundof claim 6 wherein Y is alkyl, alkyloxyalkyl, cycloalkyl,tetrahydropyran-4-yl or tetrahydropyran-2-yl.
 11. The compound of claim7 wherein R² and R⁴ are hydrogen, Y is isopropyl, and m is the integer0.
 12. The compound of claim 11 wherein the pharmaceutically acceptablesalt is selected from hydrochloride, sulfate or oxalate, or a crystalform thereof.
 13. The compound of claim 12 wherein the pharmaceuticallyacceptable salt is sulfate or a crystal form thereof.
 14. The compoundof claim 13 wherein the crystal form is selected from Form I or Form 11.15. The compound of claim 14 wherein the crystal form is Form Icharacterized by the following X-ray powder diffraction patternexpressed in terms of “d” spacings and relative intensities (IR):d,10⁻¹⁰ m RI, % 31.084 100 10.266 4 7.686 39 5.546 4 5.451 3 5.118 104.838 10 4.767 13 4.744 13 4.391 3 4.179 9 4.149 9 3.947 7 3.898 6 3.8384 3.697 6 3.554 3 3.408 3


16. The compound of claim 14 wherein the crystal form is Form IIcharacterized by the following X-ray powder diffraction patternexpressed in terms of “d” spacings and relative intensities (IR):d,10⁻¹⁰ m RI, % 25.664 100 12.756 3 6.386 49 4.397 7 4.258 9 4.088 33.910 4 3.307 4


17. The compound of claim 4 wherein R³ is —O(CH₂)_(n)Z wherein n is aninteger from 1 to
 4. 18. The compound of claim 17 wherein Z iscycloalkyl, heterocyclyl or hydroxyalkyl.
 19. The compound of claim 18wherein Z is cyclopentyl, cyclohexyl, heterocyclyl or hydroxyalkyl. 20.The compound of claim 18 wherein Z is cycloalkyl, tetrahydropyran-4-ylor tetrahydropyran-2-yl, or hydroxyalkyl.
 21. The compound of claim 18wherein Z is cycloalkyl, heterocyclyl or 1-hydroxymethyl.
 22. Thecompound of claim 4 wherein R³ is —(CH₂)_(m)SO₂NR⁸R⁹ or—(CH₂)_(m)SO₂NR⁸R⁹ wherein m is an integer from 0 to
 3. 23. The compoundof claim 22 wherein R⁸ is hydrogen or alkyl, and R⁹ is alkyl orarylalkyl.
 24. The compound of claim 23 wherein R⁸ is hydrogen, methyl,ethyl or propyl, and R⁹ is methyl, ethyl, propyl, isopropyl, n-butyl,isobuty, sec-buty, tert-butyl or arylalkyl.
 25. The compound of claim 23wherein R⁸ is hydrogen, methyl, ethyl or propyl, and R⁹ is alkyl orbenzyl.
 26. The compound of claim 4 wherein R³ is —(CH₂)_(m)NR⁷SO₂R⁹ or—(CH₂)_(m) NR⁷COR⁹ wherein m is an integer from 0 to
 3. 27. The compoundof claim 26 wherein R⁷ is hydrogen or alkyl, and R⁹ is alkyl, aryl orarylalkyl.
 28. The compound of claim 27 wherein R⁷ is hydrogen, methyl,ethyl or propyl, and R⁹ is methyl, ethyl, propyl, isopropyl, n-butyl,isobuty, sec-buty, tert-butyl, aryl or arylalkyl.
 29. The compound ofclaim 27 wherein R⁷ is hydrogen, methyl, ethyl or propyl, and R⁹ isalkyl, phenyl or arylalkyl.
 30. The compound of claim 27 wherein R⁷ ishydrogen, methyl, ethyl or propyl, and R⁹ is alkyl, aryl or benzyl 31.The compound of claim 3 where R¹ is a group represented by formula (B)wherein X is S.
 32. The compound of claim 31 wherein R³ is (CH₂)_(m)OYwherein m is an integer from 0 to
 3. 33. The compound of claim 32wherein Y is alkyl, alkyloxyalkyl, cycloalkyl or heterocyclyl.
 34. Thecompound of claim 33 wherein Y is methyl, isopropyl, isobuty, sec-butyl,tert-butyl, alkyloxyalkyl, cycloalkyl or heterocyclyl.
 35. The compoundof claim 33 wherein Y is alkyl, 2-ethoxy-1-(ethoxymethyl)ethyl,cycloalkyl or heterocyclyl.
 36. The compound of claim 33 wherein Y isalkyl, alkyloxyalkyl, cyclopentyl, cyclohexyl or heterocycylyl.
 37. Thecompound of claim 33 wherein Y is alkyl, alkyloxyalkyl, cycloalkyl,tetrahydropyran-4-yl or tetrahydropyran-2-yl.
 38. The compound of claim31 wherein R³ is —O(CH₂)_(n)Z wherein n is an integer from 1 to
 4. 39.The compound of claim 3 where R¹ is a group represented by formula (C)wherein X is N.
 40. A compound of Formula I selected from:2-[4-(4-isoproxybenzyl)phenyl]amino-imidazoline,2-{4-[4-(sec-butoxy)benzyl]phenyl}amino-imidazoline,2-{4-[4-(cyclopentyloxy)benzyl]phenyl}amino-imidazoline,2-{4-[4-(tetrahydropyran-4-yloxy)benzyl]phenyl}amino-imidazoline,2-{4-[4-(tetrahydropyran-4-ylmethoxy)benzyl]phenyl}amino-imidazoline,2-{4-[4-(tetrahydropyran-2-ylmethoxy)benzyl]phenyl}amino-imidazoline,2-{4-[2-fluoro-4-(tetrahydropyran-4-ylmethoxy)benzyl]phenyl}amino-imidazoline,2-{4-[4-(2-ethoxy-1-(ethoxymethyl)ethoxy)benzyl]phenyl}amino-imidazoline,2-[4-(4-cyclopentyloxythienyl-2-ylmethyl)phenyl]amino-imidazoline,2-{4-[4-(4-methoxyphenyl)sulfonylmethylamino-ethoxybenzyl]phenyl}amino-imidazoline,2-{4-[4-(1-hydroxymethyl-ethoxy)benzyl]phenyl}amino-imidazoline,2-[4-(5-methoxythienyl-2-ylmethyl)phenyl]amino-imidazoline,2-[4-(4-butylaminosulfonylbenzyl)phenyl]amino-imidazoline,2-[4-(4-isoproxymethylbenzyl)phenyl]amino-imidazoline,2-[4-(4-sec-butoxymethylbenzyl)phenyl]amino-imidazoline,2-{4-[4-(isobutylaminosulfonyl)benzyl]phenyl}amino-imidazoline,2-[4-(4-benzylaminocarbonylbenzyl)phenyl]amino-imidazoline,2-[4-(4-isopropylaminosulfonylbenzyl)phenyl]amino-imidazoline,2-[4-(4-isobutylaminocarbonylbenzyl)phenyl]amino-imidazoline, or2-[4-(4-tert-butylaminosulfonylbenzyl)phenyl]amino-imidazoline.
 41. Acompound of claims 1, 4, 31, 39 or 40 wherein the pharmaceuticallyacceptable salt is selected from hydrochloride, oxalate or sulfate, or acrystal form thereof.
 42. A process for preparing a compound of claim 1comprising reacting a compound of the formula:

with a compound of the formula:

or an acid addition salt thereof, in which L is a leaving group.
 43. Theprocess of claim 42 where the compound of the formula:

is an acid addition salt thereof.
 44. A pharmaceutical compositionsuitable for administration to a mammal having a disease state that isalleviated by treatment with an IP receptor antagonist, whichcomposition comprises as an ingredient a therapeutically effectiveamount of a compound of claims 1, 4, 31, 39 or 40, or a pharmaceuticallyacceptable salt or a crystal form thereof, in admixture with at leastone pharmaceutically acceptable non-toxic carrier.
 45. A pharmaceuticalcomposition suitable for administration to a mammal having a diseasestate that is alleviated by treatment with an IP receptor antagonist,which composition comprises as an ingredient a therapeutically effectiveamount of a compound of claims 15 or 16, in admixture with at least onepharmaceutically acceptable non-toxic carrier.
 46. A method for treatinga mammal having a disease state that is alleviated by treatment with anIP receptor antagonist, which comprises administering a therapeuticallyeffective amount of a compound of claims 1, 4, 31, 39 or 40, or apharmaceutically acceptable salt or a crystal form thereof.
 47. Themethod of claim 46 wherein the disease state is independently selectedfrom pain, inflammation, urinary incontinence, asthma or septic shock.48. The method of claim 47 wherein the disease state is pain.
 49. Themethod of claim 48 wherein the disease state is selected from surgicalpain, visceral pain, dental pain, premenstrual pain, central pain, paindue to burns, migraine or cluster headaches, nerve injury, neuritis,neuralgias, poisoning, ischemic injury, interstitial cystitis, cancerpain, viral, parasitic or bacterial infection, post-traumatic injuries,or pain associated with functional bowel disorders.
 50. The method ofclaim 47 wherein the disease state is inflammation.
 51. The method ofclaim 50 wherein the disease state is selected from bacterial, fungalinfections, viral infections, rheumatoid arthritis, osteoarthritis,surgery, bladder infection, idiopathic bladder inflammation, over-use,old age, nutritional deficiencies, prostatis, or conjunctivitis.
 52. Themethod of claim 47 wherein the disease state is urinary incontinence.53. The method of claim 52 wherein the disease state is selected fromurge incontinence, stress incontinence, or bladder hyperreactivity. 54.The method of claim 47 wherein the disease state is asthma.
 55. Themethod of claim 47 wherein the disease state is septic shock.
 56. Amethod for treating a mammal having a disease state that is alleviatedby treatment with an IP receptor antagonist, which comprisesadministering a therapeutically effective amount of a compound of claims15 or
 16. 57. The method of claim 56 wherein the disease state isindependently selected from pain, inflammation, urinary incontinence,asthma or septic shock.
 58. The method of claim 57 wherein the diseasestate is pain.
 59. The method of claim 58 wherein the disease state isselected from surgical pain, visceral pain, dental pain, premenstrualpain, central pain, pain due to burns, migraine or cluster headaches,nerve injury, neuritis, neuralgias, poisoning, ischemic injury,interstitial cystitis, cancer pain, viral, parasitic or bacterialinfection, post-traumatic injuries, or pain associated with functionalbowel disorders.
 60. The method of claim 57 wherein the disease state isinflammation.
 61. The method of claim 60 wherein the disease state isselected from bacterial, fungal infections, viral infections, rheumatoidarthritis, osteoarthritis, surgery, bladder infection, idiopathicbladder inflammation, over-use, old age, nutritional deficiencies,prostatis, or conjunctivitis.
 62. The method of claim 57 wherein thedisease state is urinary incontinence.
 63. The method of claim 62wherein the disease state is selected from urge incontinence, stressincontinence, or bladder hyperreactivity.
 64. The method of claim 57wherein the disease state is asthma.
 65. The method of claim 57 whereinthe disease state is septic shock.